CHAPTER 28: STRUCTURE-ACTIVITY RELATIONSHIP AND DRUG DESIGN 469

CHAPTER 28 the activity of the n-alkylresorcinols in which the optimum bio- anesthetics. The carbomethoxy group of cocaine is not required
logical activity, as measured by phenol coefficients against B ty- for local anesthetic action, as can be seen with tropacocaine,
Structure–Activity Relationship phosus, is hexylresorcinol (1) which lacks this group (5).

and Drug Design

Randy J Zauhar

with six carbon atoms (n ! 5) in the side chain. If the alkyl

chain is lengthened or decreased, a decrease in activity is
observed relative to hexylresorcinol.
There are times in which changing the number of methylene
groups may lead to a change in the type of biological activity The synthesis of "-eucaine (6)
rather than its intensity. For example, it is known that
alkyltrimethylammonium analogs (2)

For centuries humans have observed not only that natural sub- ANALOG APPROACH
stances could be used for their nutritional value and for treat-
ment of diseases, but they could also bring about toxic or lethal The most frequent approach to obtaining drugs to treat a par-
effects. The Chinese Emperor Sheng Nang in 2735 BCE ticular disease is to synthesize analogs of drugs that are known
compiled a book of herbs and employed Chang Shan in the to be effective in the treatment of the disease. The pharma-
treatment of malaria. Although the majority of the drugs used cophore is a chemical segment of a molecule that is responsible and subsequent biological testing showed that a tropane ring
from antiquity to the 19th century came from natural sources, for biological action. Normally, it is found that the specific type system also was not a prerequisite for local anesthetic activity.
in the past century a new era was brought about by treatment of biological activity of a molecule depends on more than just possess different types of activity depending on the length of The synthesis of procaine (7)
of diseases with synthetic drugs. Also, the modification of one functional group. Consequently, the addition of a single the alkyl group.
natural products, through various synthetic processes, has functional group to an inert organic substance ordinarily does If the alkyl group is up to six carbons (n ! 5), as in 2, the
provided useful semisynthetic drugs. not imbue a molecule with a specific biological activity because compounds are muscarinic agonists. Thus, these compounds
The field of medicinal chemistry has evolved from an em- more than one functional group normally is required for potent have activity similar to acetylcholine (3)
phasis on the synthesis, isolation, and characterization of drugs activity, and in addition these must usually be arranged with a
to an increased awareness of the biochemistry of disease states specific geometry.
and the design of drugs for the prevention of diseases. An im- Drug activity depends on the size, shape, and degree of ion-
portant aspect of medicinal chemistry has been to establish a ization of the drug molecule. These parameters are studied demonstrated that the critical part of the molecule required for
relationship between chemical structure and biological activity. by making analogs or molecular modifications of a parent activity was the hydrophilic amine segment attached to an
An increased consideration in recent years has been to correlate molecule. In those instances where a molecule has a known bio- intermediate chain, which in turn was attached to a lipophilic
the chemical structure with chemical reactivity or physical logical action, this substance serves as a prototype or lead ester function. Many analogs of procaine have potent local anes-
on muscarinic receptors. With seven carbons (n ! 6) to eight
properties and these correlations can, in turn, be related to molecule for the synthesis of analogs for further biological test- thetic activity. The amine section of procaine can be removed to
(n ! 7) carbons, these compounds are partial agonists; when
their therapeutic actions. ing. In the past this process has produced a greater number of ac- give benzocaine (8),
the length is greater than nine carbons (n ! 8), these com-
Although there has been a great deal of success in under- tive analogs than just preparing and testing molecules obtained pounds are muscarinic antagonists.
standing the relationship between chemical structure and through a random process. In addition, structure–activity rela-
biological activity in a number of areas, especially for antibacte- tionship studies often are used to determine the pharmacophore
rial drugs, there are still many human afflictions that require and also to obtain drugs with increased potency, greater selec-
new and improved drugs. Cancer, viral infections, cardiovascu- tivity, increased or decreased duration of action, low toxicity, and
lar disease, and mental disease need new agents and approaches increased stability. Molecular Fragmentation
for treating and preventing these maladies. As more informa- Finally, economics may be a prime reason for the search for
tion is gained as to causative factors of different diseases, the analogs if a natural product is too difficult to obtain or if a syn- The synthesis and biological evaluation of molecular fragments a substance known to possess local anesthetic activity. How-
move will be from the empirical approach to the rational design thetic molecule is too expensive to prepare in quantities needed of a lead compound often is used in structure–activity studies. ever, the mechanism of action of benzocaine in the produc-
of new drugs. General principles of drug design have been and for the manufacturing process. This process also may be called molecular simplification, molec- tion of local anesthesia is different from that of procaine.
are continuing to be developed in medicinal chemistry. ular dissociation, or disjunction. Often, this process is used Therefore, one must be cautious in relating chemical changes
In developing drugs with specific activities, several ap- when the structure of a natural product is elucidated and the to activity, particularly because the drug may retain activity
proaches are used. The effects of natural products or synthetic molecule has an important and possibly new biological action. but the mechanism by which the activity is produced may
drugs are determined on various biological systems (or screens)
Homologs When the natural product may be too difficult or expensive to change.
to identify lead compounds with specific biological activities. A homologous series refers to a series of analogs that differ in obtain for drug use, the process of trial and error is used to Vitamin K1 (9)
Once the effect of the drug is known, the medicinal chemist and structure by a simple increment in the molecular formula. For determine which portion of the molecule is required for a de-
pharmacologist work together to improve the activity of a known example, these may be produced by sequential chemical change sired biological activity. Several illustrations of the molecular
active molecule or “lead molecule.” This process normally goes that includes increasing or decreasing the length of a carbon fragmentation approach will be given in which the starting
through a synthesis—biological test—synthesis—biological test chain. A series of homologs of this type is used to provide insight point is a natural product.
cycle until a drug with the desired activity is obtained. Today, into the relationship of biological activity and chemical changes Cocaine (4),
the structure of receptors and function of enzymes, which may that involve only the number of methylene groups. This type of
be involved in the pathogenesis of a disease, are understood bet- determination has provided valuable information as to the im-
ter. These molecules, in turn, are used as targets for the design portance of the partition coefficient and biological action. Often,
of drugs that act as agonists or antagonists of receptors or in- the compounds with short, alkyl chains are low in activity; as the
hibitors of the enzymes. Thus, this information adds a new chain length is increased, the biological activity increases to an
phase to the cycle, which is now drug design—synthesis— optimum point, and as more methylene groups are added, ac-
biological activity—drug design, and so on. tivity decreases. An interesting example of this phenomenon is
is a natural product (phytonadione) composed of a naphtho-
quinone bearing a 2-methyl group and a side-chain phytyl
group at the 3 position. It is known that vitamin K is useful in
preventing hemorrhage and attempts have been made to pre-
an alkaloid obtained from Erythroxylon coca, has served as the pare drugs that were less complex but maintained vitamin K
468 prototype molecule for the development of a number of local activity.
470 PART 3: PHARMACEUTICAL CHEMISTRY CHAPTER 28: STRUCTURE-ACTIVITY RELATIONSHIP AND DRUG DESIGN 471

Menadione (10) a bicyclic, meperidine (15); changed to an N-allyl group as shown in 19, Table 28-1. Isosteric Replacements
CLASS 1 2 3 4 5
(MONOVALENT) (DIVALENT) (TRIVALENT) (TETRAVALENT) (RINGS)

F, Cl, Br, I MOM MNB BCB MCHBCHM

OH, SH MSM MPB BSiB MSM
NH2, PH2 MSeM MAsB BN%B MOM
CH3 MTcM MSbB BPB MNHM
MCHB BAsB
BSb%B

and to (16), methadone,

is a highly active, vitamin K–like drug that can be prepared to produce N-allylnormorphine (nalorphine), a morphine an-
by the oxidation of 1-methylnaphthalene with chromic acid. It tagonist. This finding has stimulated a great deal of study of
is an analog of vitamin K that lacks the phytyl side chain at structure–activity relationships with the N-substituents to find
the 3 position. A bisulfite-addition product, menadione sodium potent agonists, antagonists, and mixed agonist-antagonists of
bisulfite (11), opioid receptors. to give 5-fluorouracil (23), a very useful anticancer drug; and
In other drug categories, it has been shown that tolazo- the replacement of the carbonyl oxygen in hypoxanthine (24) to
line (20) give 6- mercaptopurine (25),

which has only the A ring of morphine remaining, but still re-
tains potent analgesic activity. Certainly, the amine and aro-
matic ring play an important role in the production of analgesic
activity. The intermediate carbon atoms between the amine
and the phenyl ring do not have to be in a specific configuration is an antagonist of #-adrenergic receptors, while the addition of
is available as a water-soluble anticoagulant. The substance is
for the molecule to possess analgesic activity. another phenyl ring produces naphazoline (21),
known to decompose under appropriate conditions to liberate a potent antitumor antimetabolite. The replacement of oxy-
menadione, the free quinone (10). gen by sulfur in chlorpromazine (26) to give the oxygen
Another area in which molecular fragmentation has led isostere (27)
to the development of a number of useful drugs is with the
Addition of Functional Groups
analgesics related to morphine. The structure of morphine was Another approach often used in structure–activity relationships
determined in 1925; subsequently, many analogs were pre- is to add functional groups to a molecule with known biological
pared and examined for analgesic activity. In most instances activity. This approach was used by Bently and Hardy1 to see if
new analogs were prepared with the goal of possibly separat- a molecule more complex than morphine could be synthesized
ing the analgesic effects from the undesirable effects of that would interact with the analgesic receptor but, because of
dependence liability, nausea, constipation, and respiratory its complex structure, would not interact with the receptors that which is an #-adrenergic agonist. This is a rather unusual
depression. produced side effects. One of the analogs, etorphine (17), transformation of an antagonist into an agonist by the addition
It can be seen that, through molecular fragmentation, one of a functional group.
can reduce the number of ring systems from the pentacyclic, produced a compound with 1/10 the tranquilizing activity of the
parent molecule.
morphine (12) Isosteric Replacements The replacement of the ester function of procaine (7), a
The concept of isosterism or bioisosterism has been used for a local anesthetic, with an amide function produced pro-
number of years in the search for new drugs. This has been an cainamide (28),
extremely important approach in the design of antimetabolites.
In 1919, Langmuir2,3 first defined isosteres as those molecules or
groups of atoms that have the same number and types of elec-
trons. For example, N2 and CO or N3$ and NCO$ are examples
of isosteres. These substances have similar physical properties.
is some 1000 times more potent than morphine and is used pri- Later, Friedman4 introduced the concept of bioisosteres, com-
marily in veterinary medicine to immobilize large animals. Of pounds that fit the broadest definitions for isosteres and have a
major importance is the fact that etorphine and related agents similar type of biological activity. This concept included drugs which has found an important role in the treatment of cardiac
have enhanced potency, suggesting that etorphine may bind to with agonist or antagonist activity. When a substance is found arrhythmias. An important difference between the two drugs is
to a tetracyclic, levorphanol (13), an additional site that dramatically enhances the analgesic that does possess promising therapeutic activity, the medicinal that the amide function, which allows for similar biological
activity of morphine. chemists will attempt to prepare closely related compounds with activity, is more stable chemically, can be given orally, and is
It also is known that replacement of the N-methyl group improved properties such as greater potency or fewer side ef- not affected by the esterases that catalyze the hydrolysis of
with the larger N-phenethyl group to give N-phenethylnor- fects. In the past, a considerable amount of intuition had been procaine.
morphine (18) used by medicinal chemists in selecting bioisosteric replace- The antibiotic puromycin (29),
ments. The standard isosteric replacements are divided into five
classes, as illustrated in Table 28-1.
A variety of nonclassic bioisosteric replacements also are
known and include paired examples such as H and F, MCO2H
and MSO3H and MCOM and MSO2M.
Some of the examples of isosteric replacement that have
and a tricyclic, pentazocine (14), provided useful drugs are a fluorine replacement of the hydro-
gen in uracil (22)

produces a compound six times as potent as morphine. An im-

portant observation is that not only may a quantitative change which has antibacterial, antitumor, and antitrypanosomidal
be brought about by modifying the N-methyl group of morphine activity, inhibits protein synthesis by interfering with the uti-
but also a qualitative change in activity is observed if it is lization of transfer-RNA. Puromycin is the isosteric analog of
472 PART 3: PHARMACEUTICAL CHEMISTRY CHAPTER 28: STRUCTURE-ACTIVITY RELATIONSHIP AND DRUG DESIGN 473

the aminoacyl-t-RNA (30); and amobarbital (37), both of which belong to the barbitu- isomer of epinephrine (44) can exist in an infinite number of conformations about the side-
rate family. These positional isomers differ only in the chain carbon–carbon bond. Two such conformations are illus-
makeup of the 5-carbon side chain attached to the barbitu- trated [( ! 60° gauche and ( ! 180° trans conformation (49B
rate ring system. The former compound has a short duration and C)].
of action while the latter has an intermediate duration of Apomorphine (50)
action.
Another example of positional isomers is N-(tert-butyl)-
norepinephrine (38)

after puromycin is taken up, it blocks the subsequent protein

synthesis. and 6,7-dihydroxy-2-aminotetralin (ADTN) (52)
The isosteric replacement of ester groups does not always is more potent on both #- and "-adrenergic receptors than the
produce compounds with significant biological activity, as the S(%) isomer (45). The binding of the isomers of epinephrine and
modification of acetylcholine ester (3) with an amide function and terbutaline (39). The resorcinol portion of 39 has served
as a biologically effective replacement of the catechol group epinine (46) (the desoxy analog of epinephrine) is illustrated. The
resulted in the amide analog (31) three points of binding on the receptor are the catechol binding
in 38. The resorcinol analog (39), in contrast to the cate-
chol (38), is not a substrate for catechol-O-methyltransferase site (A), hydroxy binding site (B), and anionic binding site (C).
(COMT), an important metabolic enzyme; therefore, it has According to the Easson–Stedman theory,5 the relative
a longer duration of action. Terbutaline is a useful selec- order of activity of the isomers on adrenergic receptors are R &
tive "2-adrenergic stimulant for the treatment of bronchial S ! deoxy. Only the R isomer can bind to all three sites,
are two potent dopamine D1 and D2 agonists that exist in the
asthma and related conditions, and it can be administered whereas both the S isomer and the deoxy isomer, which show
trans conformation, whereas the selective D1 agonist SKF
orally. similar activity, can bind only to two of the sites. Refer to Chap-
38393 (51) does not exist in a similar conformation. Apomor-
that does not show significant agonist or antagonist activity. One Geometrical isomers are another important set of mole- ter 13 for a discussion of isomerism.
phine, a conformationally rigid molecule, can bind to both D1
of the oldest nonclassic isosteric replacements that provided an cules in which a possible difference in biological activity Although enantiomers have the same chemical and physical
and D2 dopamine receptors.
important class of antibacterial agents was the replacement of between isomers may exist. The trans, or E, isomer of tripro- properties, except for the direction of rotation of polarized light,
In other instances, a drug molecule may need conforma-
carboxylic acid group of p-aminobenzoic acid (PABA, 32) lidine (40) diastereomers have different physical properties. Diastere-
tional flexibility for proper binding to the receptor to produce
omers are compounds with two or more chiral centers. While
biological activity in an induced-fit receptor model. Thus, con-
1R,2S($)-ephedrine (47)
formational flexibility may in some instances be a prerequisite
for drug agonist activity.

with a sulfonamide group to give sulfanilamide (33). Ionization

A final illustration of bioisosteric replacement in drug de-
Many of the substances used as drugs are weak acids or weak
sign is the replacement of the thiourea functional group of
bases. Therefore, an important question is whether the charged
metiamide (34),
or uncharged form of the drug binds to the receptor. Also of im-
portance is the degree of ionization and the effect ionization
is over 1000 times as potent as the cis, or Z, isomer (41) has direct activity on both #- and "-adrenergic receptors, may have upon absorption and distribution. In general, the ion-
as a H1-histamine antagonist. Another example of a set of ge- the 1R,2R ($)-'-ephedrine (48) shows #-adrenergic blocking ization can be demonstrated as
ometrical isomers is the cis and trans-2-acetoxycyclopropy- activity. Both diastereomers show indirect adrenergic activity.
ltrimethyl ammonium iodides (42 and 43), An important strategy often used in drug design is to take
a conformationally flexible molecule and to convert it into a con-
a histamine H2-blocker, with the cyanoguanidine group to pro- formationally rigid molecule in order to find the optimum
duce the popular antiulcer drug cimetidine (35). This bioisos- conformation for binding to a drug receptor. This approach may
teric replacement overcame the granulocytopenia toxicity that be used to introduce selectivity for receptors, eliminate unde-
had been observed with metiamide. sired side effects, and learn about the spatial relationships of
functional groups for receptors. It is very difficult to know which molecular form of the
Dopamine (49A) drug is active if the charged and uncharged forms are in equi-
Stereochemistry librium in physiological solution; for example, with dopamine
An important consideration in drug–receptor interactions is the pKa of the amine is !10. Thus, although most of the drug
the stereochemistry of the drug and the proper positioning of in solution is in the ionized form (49D), the un-ionized form of
functional groups so that they will interact optimally with an the drug molecule still may be the active form.
enzyme or receptor. Four types of isomeric drugs will be con- The quaternary salt of dopamine (53)
sidered: positional isomers, geometrical isomers, optical iso-
mers, and diastereomers.
With positional, or constitutional, isomers the compounds
have the same empirical formula but the atoms of the molecule
are rearranged in a different order. To illustrate positional iso-
mers, one can consider the relationship of pentobarbital (36)

respectively. The trans isomer is much more potent as a mus-

carinic agonist than the cis isomer and also is a good substrate has been prepared and exhibits agonist activity on D2-recep-
for the enzyme acetylcholinesterase. tors, indicating that the ionized form of the drug is an active
The term absolute configuration refers to the arrangement molecular species. However, it is almost impossible to deter-
of atoms in space of a chiral compound. In a number of in- mine if a primary, secondary, or tertiary amine is active as the
stances there is a distinct difference in biological activity of un-ionized form of the drug because these amines are always in
the optical isomers (enantiomers). For example, the R($) equilibrium under physiological conditions.
474 PART 3: PHARMACEUTICAL CHEMISTRY CHAPTER 28: STRUCTURE-ACTIVITY RELATIONSHIP AND DRUG DESIGN 475

It has been shown that the permanently charged dimethyl- colligative properties all affect the transport process. Other fac- the drug; the volatile compounds (ether, alcohol) excrete via the without the necessity of synthesizing and measuring Px of the
sulfonium analog (54) tors that complicate the transport process include complexation lungs, poorly absorbed or insoluble substances through the GI actual compound. An example was the calculation of Px values
or protein-binding. Most drugs move through a membrane by a tract with the feces, and very few through the skin. The main for a series of substituted benzeneboronic acids. The values of *
simple diffusion mechanism (passive transport); a few com- route of elimination is through the kidney. The biochemical as- were taken from the known series of substituted benzoic acids
pounds that resemble normal body substrates may bind to pects relating to the complexity of the biosystem that the drug and, when added to the log PH value for benzeneboronic acid,
transport molecules and are carried via an active-transport must survive are intricate and little understood. gave values of log Px for the substituted boronic acids (58).
process in which drugs can move against a concentration gra-
dient—that is, they can be transported from a compartment of
low concentration to one of higher concentration. QUANTITATIVE STRUCTURE–ACTIVITY
METABOLISM—As soon as a drug enters the body, it be- RELATIONSHIPS
comes susceptible to a variety of metabolic processes that
is active as a D2-dopamine agonist, whereas the permanently usually detoxify the foreign substance. In addition, through A long-standing goal of workers in the area of quantitative
uncharged sulfide (55) is inactive as a D2-dopamine agonist.6 oxidation, reduction, hydrolysis, esterification, or conjugation structure–activity relationships (QSAR) has been the develop-
This suggests that the uncharged form of a dopamine agonist is the drug usually is made more water soluble, to enhance its ment of quantitative methods of determining the activities of When these values were used in a Hansch equation to predict
unlikely to produce D2-dopamine activity. It also has been found excretion from the body. However, there are instances when a a series of compounds. One of the earliest hypotheses that drug penetration into brain tissue, excellent correlation with
using this approach that both charged agonists and antagonists drug metabolite actually may be the active compound, having attempted to relate activity to a physicochemical parameter experimental values was obtained.
are responsible for binding to and activating dopamine D2-re- activity similar to the original compound. Usually, after several was the Meyer–Overton narcosis theory.8 In 1901, both men Another feature of Hansch’s work is the use of the technique
ceptors. This work, along with observations made using agents biotransformations, the modified form is excreted. working independently observed that, for general anesthetics, of regression analysis. In seeking structure–activity correlation
that interact with carboxyl groups that block dopaminergic re- The liver is the primary site of detoxification, but enzyme activity was related to the lipid/water partition coefficient; it often is not necessary to include all of the defined parameters
ceptors, indicates an ionic attraction between dopamine D2-ag- processes also may occur in the stomach, intestine, and other cyclopropane with a value of 65 was far more effective than in the equation to obtain good results. In effect, what has been
onists and D2-antagonists and their target receptor. areas in the body. The metabolic reactions occurring in the liver nitrous oxide with a coefficient of 2.2. done is to fit the data to several forms of the equation using the
In order to improve on the pharmacological activity of a drug traditionally are separated into two categories. In the field of theoretical chemistry, Hammett9 was the first method of least squares, to determine which equation is statis-
or to enhance metabolic stability, various replacements of acid to demonstrate that the pKa values of substituted benzoic acids tically the best. Thus, if good correlation can be obtained by in-
and basic groups have been attempted. One of the bioisosteric 1. The drug undergoes what might be termed functional-group could be predicted as a function of the various substituents at- cluding only * values, it is probable that the electronic effect of
replacements of an acid functional group often employed is that changes, such as ring or side-chain hydroxylation, nitrogroup re- tached to the ring and their abilities to either donate or with- the substituent is not critical for drug activity in that series.
of the tetrazole group, which has a pKa ! 4.9. It was found that duction, aldehyde oxidation, dealkylation, or deamination. draw electrons from the carboxyl group. These results then Postulates as to specific drug mechanisms thus can be made
the tetrazole analog (56) 2. The drug undergoes what is called conjugation, in which the me- were extended to other reactions and other series of compounds when activity dependence, or lack thereof, is found for a given
tabolized compound combines with solubilizing groups such as using the same substituent constants derived from the benzoic parameter. Further expansions of the equation also permit
glucuronic acid or glycine to form excretable conjugates. acid series. In the Hammet equation, mechanistic considerations to be formulated. The p) term (ac-
Because drugs can undergo such a wide variety of chemical tually a log k term) can be expanded to include a steric param-
log k/k0 ! p) (1)
changes in the body, the specifics of which are unpredictable, eter (Es) or electron-density parameters for various parts of a
the medicinal chemist must at least be aware of these metabolic where k is the rate constant for the reaction of a substituted molecule. Thus, if inclusion of a steric substituent constant
processes. At some point in the development of a new drug, the aromatic compound, k0 is the rate constant for the unsubsti- leads to improved correlation, the steric requirements of the
molecular structure of the drug may have to be altered in order tuted aromatic compound, p is the reaction constant, and ) is drug/enzyme interaction can be better understood. Several ex-
to change the way in which it is metabolized. the substituent constant. Later work led to substituent con- amples are given below for derived equations in which excellent
of nicotinic acid (57) was more active as an antihyperlipidemic INTERACTION WITH ACTIVE SITES—Ehrlich7 first stants in which the electronic effect is separated into inductive correlation with experimental results is found when one or
than the parent molecule, nicotinic acid. introduced the concept that a drug must first combine with a re- and resonance terms; in the Taft equation, a term Es is defined more parameters are omitted.
ceptor (active site) to produce an effect. A receptor is considered as a measure of the steric requirements of a substituent. For the antibacterial effects on gram-negative bacteria of a
to be a cellular substance on which a drug acts to produce its ef- In more recent times there have been numerous mathemat- series of diguanidines, the structures of which are shown in 59,
Drug Disposition fects. A receptor may be composed of protein, RNA, or DNA. ical attempts to correlate molecular structure with drug activ-
It should be recognized that a number of factors can affect the Proteins are an important set of receptors, and drug action may ity. Many of these attempts were destined to fail because they
interaction of a drug with a receptor, including interatomic dis- be a consequence of the influence of a drug on an enzyme. Of- grossly oversimplified what is now known as a very complex
tances, shape, size, absolute configuration, rigidity, flexibility, ten, the drugs reserved for cancer and viral diseases interact problem, even more so than simple chemical reactivity. Moder-
and charge distribution. Some or all of these factors play a part with DNA. ate success has been achieved within narrow limits of drug
in the consideration of drug design. Normally, by starting the An enzyme system is composed of a coenzyme, usually non- type, but a universal equation has yet to find expression.
drug-design process at the level of receptors or enzymes, the protein in nature; an apoenzyme (the protein portion), which One of the most successful investigators in this field is Han-
variables such as absorption, transportation, metabolism, and also may enjoin a nonprotein prosthetic group; and cofactors, of- sch,10 who derived a general equation based on linear free-en- the equation
excretion are set aside temporarily in order to optimize affinity ten inorganic metallic ions and the substrate, which is acted ergy considerations. Inherent in this equation is the ability to log 1/C ! $0.081 *2 % 1.483* $ 1.578 (4)
and potency. Regardless of how the medicinal chemist chooses upon by the enzyme. The active site on the enzyme may consist incorporate parameters that encompass the full range of known
to modify the structure, the process of developing a drug is very of an anionic, cationic, acidic, basic, and/or neutral sites. In ad- biological requirements for drug activity. Among these are predicts quantitative activity very accurately. Substituent ef-
complex and the additional factors that must be considered in dition, the physical shape of the site is such that the contour of terms for biological transport, drug/enzyme binding energies, fects are neglected here because molecular modification in-
obtaining a useful drug will be discussed below. the molecule that interacts with the receptor must have a substituent effects (both electronic and steric), and electron volves only a change in the number of methylene groups.
ABSORPTION—Most drugs are administered orally and proper shape to insure a fit on the receptor. densities of possible active sites on the drug molecule. For the antibacterial activity of substituted phenols of the
pass through the stomach, small intestine, and colon; they may BINDING AND STORAGE—It is known that other sub- The most general form of the Hansch equation usually is structure indicated by 60, the equation
be absorbed at any location. During their passage through the stances, including mucins and proteins, bind drugs. If the bind- written
log 1/C ! 0.684 log P $ 0.921) % 0.268 (5)
gastrointestinal (GI) tract, drugs will experience a range of pH ing force is strong, the drug may combine quickly with the log 1/C ! $a(log P)2 % b log P % p) %c (2)
changes starting at about 1.5 in the stomach and reaching as macromolecules and thus be removed from the transport sys- fits the data best.
high as pH 8 in the colon. Additionally, drugs are subjected to a tem, metabolized, and excreted. Besides complexation to Activity is expressed as 1/C, where C is the concentration of a It would seem that substituents that donate electrons ($)
variety of enzymes and complexing agents, all of which tend to macromolecules, storage also can occur by partitioning in the drug required to elicit a given response and P is the octanol/wa- values) would have the highest activity, but in the series stud-
reduce the effective concentration of the compound. body lipids or chelation by bony tissue. In any case, the location ter partition coefficient, a measure of the hydrophobic bonding ied, these compounds have relatively small values of log P, and
For a drug to be absorbed (through lipid membranes), it must and degree of storage is a factor influencing the potency, toxic- power of the drug. Its magnitude is indicative of the constant, this offsets much of the substituent effect. Thus, the most active
be present in the fat-soluble un-ionized form. The pKa of the ity, and duration of action of a drug. For example, the short- p, which is characteristic of a given molecular type; and ) is the compounds were those that had the best balance between par-
drug and the pH of the absorption site determine the ease of ab- acting barbiturates are thought to be bound very rapidly by Hammett substituent constant, which is a measure of the elec- tition coefficient and electronic effect.
sorption. Acidic drugs (eg, aspirin) are absorbed best from the body tissues, and thus the active species is removed quickly tronic effect on the rate of reaction. For a series of phosphonate esters known cholinesterase
stomach, whereas basic compounds (eg, ephedrine) are absorbed from the transport system and its action ceases. Yet suramin The equation also is expressed as inhibitors (61),
preferentially in the small intestine. Permanently ionized sodium has an extremely long biological half-life, with notice-
able concentrations evident months after cessation of dosing log 1/C ! $a*2 % b* % p) % c (3)
molecules (eg, quaternary ammonium salts) lack lipid solubility
and usually are absorbed poorly from any region of the GI tract. with the drug. where * ! log Px $ log PH. Px is the partition coefficient of the
TRANSPORT—The blood is the primary carrier of drugs EXCRETION—The excretion process is coupled closely to substituted molecule, and PH is the partition coefficient of the
throughout the body. Independent of the method of adminis- metabolism and results in the removal of the drug from the parent unsubstituted molecule. The particular benefit of the *
tration, the drug must pass through several membranes on its body. Elimination may occur via the kidney, liver, skin, lungs, term is the observation by Hansch that * values are additive
way to the active site. Solubility, degree of ionization, and other or GI tract. The route of excretion used is determined largely by and thus numerous partition coefficients can be calculated
476 PART 3: PHARMACEUTICAL CHEMISTRY CHAPTER 28: STRUCTURE-ACTIVITY RELATIONSHIP AND DRUG DESIGN 477

the equation that gave the best correlation was activity of a series of indane nucleosides based on molecular mustards, and other alkylating agents used for cancer
surface area and the energy of the LUMO (lowest unoccupied chemotherapy, act in this fashion. These drugs are relatively
log K ! $0.152* $ 1.68) % 4.053 Es % 7.212 (6) molecular orbital); Clare and Supuran14 built successful QSAR nonspecific inhibitors that act by forming irreversible bonds
where K is the inhibition constant, ) is the substituent con- models for the activities of a series of 36 carbonic anhydrase in- with enzyme and nucleic acid molecules. In doing so they may
stant for aliphatic systems, and Es is the Taft steric constant. hibitors using as descriptors various quantities derived from ab not block necessarily a particular site, but rather many active
Here is a series in which the steric effect of the substituents initio quantum calculations, including partial atomic charges, sites; in this way, they inactivate enzymes and react with base
plays an important role. The bulkier groups cause a decrease components of molecular dipole moment projected along key residues of DNA, to form cross-links. Nitrogen mustards can
in cholinesterase inhibition. chemical bonds, and molecular surface area. prevent replication, and thus arrest cell division.
These are just a few of the many structure–activity corre- Perhaps the most ambitious technique for directly correlat- One of the recent advances in the treatment of hypertension
lations that Hansch has been able to formulate. A study of ing molecular structure with activity is CoMFA (Comparative came about through a better understanding of the mechanism
those equations of best-fit also can give an indication of how Molecular Field Analysis). In this approach a three-dimensional of angiotension. The renin–angiotensin system (RAS) (63),
to modify a structure to affect biological activity. In a study of grid is superimposed on a set of aligned molecules (usually a con-
thyroxine derivatives, it was predicted (and substantiated) generic series, but not necessarily so), and electrostatic and
that the replacement of iodine by a t-butyl group should lead steric potentials for the molecules are computed at each vertex
to a more active molecule. To date, the Hansch equation is one of the grid. A multiple regression model is then constructed to
of the most ambitious attempts to explain drug activity in relate experimental activities with the variations in the fields
terms of structural variations. measured on the grid. The method can be used to create predic-
To obtain a good statistical correlation in fitting data to an tive models which have the added benefit of highlighting
equation that should lead to the prediction of the most active portions of the grid associated with large variations in activity
compound in a series, the more compounds that are prepared, (for example, regions where high positive electrostatic potential
the better the results. At least five compounds should be pre- is correlated with high activity). It is possible to generate color-
pared for each variable on the right side of the equation; and coded graphical displays that can serve as a guide in modifying
the greater the number of compounds synthesized, the more molecules so as to realize increased activity. CoMFA has been
Figure 28-1.
likely an optimum compound will be found. successfully applied to a wide range of molecular targets, in-
Topliss11 devised an operational scheme (62), cluding HIV protease inhibitors,15,16 androgenic compounds,17
and opioids.18

MECHANISM-BASED DRUG DESIGN Enzymes using pyridoxal phosphate have been used a great
plays a key role in the maintenance of sodium and fluid vol- deal with this approach. An example is monofluoromethyl
Theories of drug design have evolved from the concept of drug- ume, resulting in the regulation of blood pressure. The system dihydroxyphenylalanine (Fig 28-1), which inhibits the enzyme
receptor interactions. In a viable biosystem, a variety of sub- is composed of two important enzymes: renin and angiotensin- aromatic amino acid decarboxylase (AAAD). The inhibition of the
strates are known to be metabolized through the intervention converting enzyme (ACE). Renin converts angiotensinogen enzyme is shown with the cofactor in Figure 28-1. There
of enzyme systems. A large proportion of drugs are believed to to the decapeptide angiotensin I; ACE acts upon angiotensin I are many examples of kcat inhibitors, but at this time one of
act by altering the ability of the substrate to interact with the to give the octapeptide angiotensin II, which is responsi- the most-used classes of drugs therapeutically are the propargy-
enzyme or receptor. Without attempting to be comprehensive, ble for the peripheral effects leading to an elevation of blood lamine derivatives, which inhibit monoamine oxidase (MAO).
extensions of the drug-receptor concept that have some experi- pressure. The inhibitors form a covalent bond with the flavine portion
mental verification will be discussed. Although ACE was identified in the mid-1950s, it wasn’t of MAO.
The theory of metabolite antagonism, or antimetabolites, is until 1977 that Cushman and Ondetti20 reported a new drug,
one that has gained credence. An antimetabolite can, through captopril (64), that competitively could inhibit ACE. This
structural or functional group similarity, compete with a provided a major advance in the treatment of hypertension. COMPUTER USE IN DRUG DESIGN
metabolite by blocking a site on an enzyme at which the Based on the concepts learned from a knowledge of the bind-
metabolite ordinarily acts. This latter mechanism, enzyme ing points of captopril—that the mercapto group binds to Zn One of the early uses of computer-assisted drug design
inhibition, probably has been studied more than any other sin- ion, the amide carbonyl to a hydrogen-bonding site, and the (CADD)21 was in the QSAR approaches of Hansch, as previ-
which shows the beginning steps in this decision-tree approach) gle mechanism. In its most recent version the theory postulates carboxylate to a positive center on the enzyme—new inhibitors ously discussed. Other uses of the computer have been to ap-
for the optimization of compounds using the substituent con- that there are sites of particular conformation on the surface of have been synthesized. One of the most successful of these new ply computational chemistry to learn about the shape of
stants * and ) values used in the Hansch method. However, the enzyme. Spacing and chemical affinity are such that only a analogs is enalaprilat (65), molecules. In conformational studies, molecular mechanics
this approach avoids the mathematical and statistical require- molecule having a shape that is the mirror image of the enzyme and quantum mechanics calculations are carried out to pro-
ments of the Hansch equation. For optimum aromatic substitu- surface and has the correct chemical groups can interact with vide insight as to the preferred conformations of a molecule. A
tion a p-chloro analog is prepared; if this is more (M) active than the enzyme. variety of approaches are used to carry out such computations.
the parent, unsubstituted compound (H), a positive * and ) The classic example of metabolite antagonism by a drug is Molecular mechanics calculations are fast, but require exten-
value is thought to be important, and the next type of substitu- sulfanilamide (33) and its derivatives. In work carried out by sive lists of atom types and detailed sets of parameters, and
tion would be a 3,4-dichloro analog. If the p-chloro analog is less Woods,19 sulfanilamide was shown to be antagonistic to p- will fail when confronted with novel chemical structures.
active (L), a 4-methoxy substituent would be the next com- aminobenzoic acid (PABA), a biological precursor of dihydrofolic On the other hand, high-level quantum calculations provide
pound to be prepared and tested; if equally (E) active, a 4- acid. A fascinating feature of these studies was the demonstra- high accuracy and can be applied to any chemical structure,
methyl substituent would be tried. Using this selection-grid tion that PABA would reverse the effect of sulfanilamide on a but are time-consuming and limited to relatively small com-
approach, the optimum compound normally can be found with bacterial culture, an example of metabolite antagonism in which has the advantage of oral activity and lacks central pounds. Fast semiempirical quantum methods ranging from
a fewer number of synthesized compounds than with the Han- reverse. Because the two compounds are isosteres, it is easy to effects. Modern approaches at preparing new drugs that will CNDO to PM3 fill an important gap, being applicable to a
sch approach. A similar type of scheme has been devised by see why they are mutually antagonistic. affect the RAS include inhibitors of renin and the preparation wide range of compounds and fast enough to be used with
Topliss for side-chain substitutions. Either the metabolite or its antagonist can attach itself to of angiotensin receptor antagonists. relatively large molecules. Although a preferred-conformation,
In recent years, advances in computing power have made the critical area of the dihydrofolate synthetic enzyme surface. Besides substrate analogs, the design of transition-state low-energy form of a drug may be calculated using these con-
possible QSAR studies that do not rely solely on experimentally- If the former occurs, PABA begins its transformation into dihy- inhibitors also is an important approach to drug design. Tran- cepts, this may not be the conformation required to produce
derived parameters that describe substituent effects, but in- drofolic acid, but if the latter happens, the metabolic process sition-state analogs are intended to resemble the substrate in drug activity.
stead compute various descriptors (HOMO and LUMO energies, ceases and, in the case of bacteria, multiplication is inhibited. transition from substrate to products, and they should be stable Molecular modeling and molecular graphics have shown
partial atomic charges, molecular dipole moment, polarizabil- The degree of inhibition depends on the relative concentrations substances. In designing this inhibitor, a very good under- dramatic growth and are becoming an integral part of the
ity) directly from the molecular wavefunction using both ab ini- of the substrate and the inhibitor. Selective toxicity is shown for standing of the specific enzyme mechanism and the chemical drug-discovery process. Molecular modeling is the generation,
tio and semiempirical methods. For example, Olivero-Verbel bacteria because mammals do not need to synthesize dihydro- nature of the transition state is needed. Another approach that manipulation, and representation of the three-dimensional
and Pacheco-Londono12 successfully modeled the cytotoxic and folic acid, but obtain it in their diets. is being used is to prepare kcat or suicide-substrate inhibitors. form of molecules; molecular graphics refers to the use of com-
anti-HIV activity of 29 flavonoids using regression models based Another mode of drug action involves enzyme deactivation In designing these types of inhibitors, the mechanism of the puter graphics to represent the molecular structure. In the
on descriptors such as atomic partial charges and total dipole without actual competition. Here, the drug can react with the enzyme should be known; it is important to generate a reactive past, synthetic chemists have used molecular models, but
moment computed using the Gaussian quantum-chemical pack- enzyme or even the enzyme-substrate complex and, in some intermediate that, in turn, undergoes an irreversible reaction computer modeling has enhanced the detailed display of
age; Yao et al13 constructed predictive models of the anti-cancer manner, prevent the metabolism of the substrate. The nitrogen with the enzyme. molecular structures.
478 PART 3: PHARMACEUTICAL CHEMISTRY

An important use of CADD is in the design of hypothetical REFERENCES

drugs. For example, when the structure of an enzyme or re-
ceptor obtained through x-ray studies is known, one can begin 1. Bently KW, Hardy DG. J Am Chem Soc 1967; 89:3269.
2. Langmuir I. J Am Chem Soc 1919; 41: 868.
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teract with the active site. Computer programs such as 4. Friedman HL. National Academy of Sciences-National Research
GOLD22 and UCSF DOCK23 allow the positions, orientations, Council Publ No 206. Washington, DC: USGPO, 1951, p 295.
and conformations of putative drug molecules to be automati- 5. Patil PN, Miller DD, Trendelenberg U. Pharmacol Rev 1974; 26: 232.
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ties to be predicted on the basis of binding energetics. A num- 7. Ehrlich P. Lancet 1913; 2: 445.
ber of graphical rendering techniques can be used to highlight 8. Doerge RF, ed. Wilson and Gisvold’s Textbook of Organic Medicinal
important interactions and features of interest, including the Chemistry and Pharmaceutical Chemistry, 8th ed. Philadelphia:
Lippincott, 1982, p 15.
use of color and representations of molecular surfaces and vol-
9. Hammett LP. Physical Organic Chemistry. New York: McGraw-Hill,
umes. This type of work, in combination with experimental 1940, p 184.
methods such as x-ray, nuclear magnetic resonance (NMR), 10. Hansch C, Fujita T. J Am Chem Soc 1964; 86:1616.
and infrared spectroscopy, should provide a powerful tool for 11. Topliss JG. J Med Chem 1972; 15:1006.
the future design of drugs. 12. Olivero-Verbel J, Pacheco-Londono L. J Chem Inf Comput Sci 2002,
42:1241.
13. Yao S-W, Lopes VHC, Fernandez F, et al. Bioorg & Med Chem 2003;
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14. Clare BW, Supuran CT. Eur J Med Chem 2000, 35:859.
DRUG DISCOVERY 15. Debnath AK. J Med Chem 1999, 42:249.
16. Nair AC, Jayatilleke P, Wang X, et al. J Med Chem 2002, 45:973.
The drug-discovery environment underwent a major evolution 17. Hong H, Fang H, Xie Q, et al. SAR QSAR Environ Res 2003, 14:373.
in the 1990s. These revolutionary changes are evident to those 18. Podlogar BL, Poda GI, Demeter DA, et al. Drug Des Discov 2000,
close to the drug-discovery process. The need for a more effi- 17:34.
cient and effective means of finding new drug molecules is one 19. Woods DD. Brit J Exp Pathol 1940; 21:74.
of a number of factors driving this new approach. Combinato- 20. Cushman DW, Ondetti MA. TIPS 1980; 1:260.
rial chemistry has shown itself to be both effective and efficient 21. Hopfinger AJ. J Med Chem 1985; 28:1133.
in both drug-lead generation and the optimization of a new 22. Jones G, Willett P, Glen RC. J Mol Biol 1995, 245:43.
drug-lead molecule. An important part of this process is the 23. Oshiro CM, Kuntz ID. J Comput-Aided Mol Design 1995, 9:113.
24. Plunkett MJ, Ellman JA. Sci Am 1997; 276(4):69.
introduction of new computing and chemical automation pro-
cesses, along with the merging of the combinatorial chemistry
with biology via high-throughput screening.
Two basic combinatorial processes are currently used.24 BIBLIOGRAPHY
Parallel Synthesis This process was invented in the 1980s by H
Mario Geysen. He used this approach initially to find the small seg- Delgado JN, Remers WA, eds. Wilson and Gisvold’s Textbook of Organic
ment of a protein that bound to antibodies. In parallel synthesis, re- Medicinal and Pharmaceutical Chemistry, 9th ed. Philadelphia:
actions are carried out separately but simultaneously using different Lippincott, 1991.
starting materials and reactants with such reactions yielding a single Foye WO. Principles of Medicinal Chemistry, 3rd ed. Philadelphia: Lea
product. Thus, using an 8 + 12 array of reaction vessels and 20 dif- & Febiger, 1988.
ferent starting materials, one can obtain a library of 96 different com- Korolkovas A, Burckhalter JH. Essentials of Medicinal Chemistry. New
pounds. Advances in robotics have allowed full automation of the rou- York: Wiley Interscience, 1976.
tine chemistry involved. Pharmaceutical companies are expanding Lien EJ. SAR Side Effects and Drug Design. New York: Dekker, 1987.
upon this process and are currently are generating thousands of new Martin YC. Quantitative Drug Design. New York: Dekker, 1978.
compounds every day. Natoff IL, Redshaw S. Drugs Future 1987; 12:475.
Split and Mix Synthesis This method24 was used in the late 1980s Nogrady T. Medicinal Chemistry. A Biochemical Approach, 2nd ed. New
by Arpad Furka. The parallel synthesis affords a single product per York: Oxford University Press, 1988.
reaction vessel, but a split and mix synthesis produces a mixture of com- Roberts GCK, ed. Drug Action at the Molecular Level. Baltimore: Uni-
pounds in each reaction vessel. This reduces the number of vessels versity Park Press, 1977.
needed per number of compounds, making it possible to prepare mil- Roberts SM, Price BJ, eds. Medicinal Chemistry. The Role of Organic
lions of compounds for a library. Split and mix synthesis has several Chemistry in Drug Research. New York: Academic Press, 1985.
complications compared to parallel synthesis; for example, it is difficult Silverman RB. The Organic Chemistry of Drug Design and Drug Action.
to keep track of the compounds in a given vessel. Furthermore, decon- New York: Academic Press, 1992.
volution of the mixture to identify the active component(s) of a mixture Smith HJ, Williams H, eds. Introduction to the Principles of Drug De-
is also difficult and time-consuming. sign. Boston: Wright, PSG, 1983.
Vallotton MB. TIPS 1987; 8:69.
The rate of discovery of new drugs has been accelerated Williams M, Malick JB. Drug Discovery and Development. Clifton, NJ:
greatly, almost beyond belief, by these new chemical technolo- Humana Press, 1987.
gies. Thus, combinatorial chemistry should increase cross- Wolff ME, ed. The Basis of Medicinal Chemistry, Burger’s Medicinal
disciplinary research and already has started an exciting era in Chemistry, 4th ed. New York: John Wiley. Part 1, 1980; Part 2, 1979;
the discovery of new drugs. Part 3, 1981.
 Chapter
2
Drug Design and Relationship
of Functional Groups to
Pharmacologic Activity
R O B I N M. Z AVO D AND J A M E S J. K N I T T E L

Abbreviations
HCl, hydrochloric acid PABA, p-aminobenzoic acid SAR, structure–activity relationship
IV, intravenous QSAR, quantitative structure–activity USP, U.S. Pharmacopeia
MW, molecular weight relationship
NaOH, sodium hydroxide

Medicinal chemistry is an interdisciplinary science at (Chapter 3). To design better medicinal agents, the rela-
the intersection of organic chemistry, biochemistry (bio- tive contribution that each functional group (i.e., pharma-
organic chemistry), computational chemistry, pharma- cophore) makes to the overall physicochemical properties
cology, pharmacognosy, molecular biology, and physical of the molecule must be evaluated. Studies of this type
chemistry. This branch of chemistry is involved with the involve modification of the molecule in a systematic fash-
identification, design, synthesis, and development of new ion followed by a determination of how these changes
drugs that are safe and suitable for therapeutic use in affect biologic activity. Such studies are referred to as
humans and pets. It also includes the study of marketed structure–activity relationships (SARs)—that is, the rela-
drugs, their biologic properties, and their quantitative tionship of how structural features of the molecule con-
structure–activity relationships (QSARs). tribute to, or take away from, the desired biologic activity.
Medicinal chemistry studies how chemical structure Because of the foundational nature of the content of
influences biologic activity. As such, it is necessary to this chapter, there are numerous case studies presented
understand not only the mechanism by which a drug throughout the chapter (as boxes), as well as at the end.
exerts its effect, but also how the molecular and physico- In addition, a list of study questions at the conclusion
chemical properties of the molecule influence the drug’s of—and unique to—this chapter provides further self-
pharmacokinetics (absorption, distribution, metabolism, study material related to the subject of medicinal chem-
toxicity, and elimination) and pharmacodynamics (what istry/drug design.
the drug does to the body). The term “physicochemical
properties” refers to how the functional groups present
INTRODUCTION
within a molecule influence its acid–base properties,
water solubility, partition coefficient, crystal structure, ste- Chemical compounds, usually derived from plants and
reochemistry, and ability to interact with biologic systems, other natural sources, have been used by humans for
such as enzyme active sites (Chapter 8) and receptor sites thousands of years to alleviate pain, diarrhea, infection,
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 30 PART I / PRINCIPLES OF DRUG DISCOVERY

and various other maladies. Until the 19th century, H3CO

O
these “remedies” were primarily crude preparations of H3C CH3
N
plant material of unknown constitution. The revolution OH
H 2 Cl
in synthetic organic chemistry during the 19th century H
produced a concerted effort toward identification of the O N
H3C H
structures of the active constituents of these naturally CH3O OH
derived medicinals and synthesis of what were hoped to
Tubocurarine
be more efficacious agents. By determining the molecu- (muscle relaxant)
lar structures of the active components of these complex CH3
mixtures, it was thought that a better understanding of N CH3 N CH3
how these components worked could be elucidated.
X

RELATIONSHIP BETWEEN MOLECULAR HO

O
OH HO O OH
STRUCTURE AND BIOLOGIC ACTIVITY
Early studies of the relationship between chemical struc- Morphine N-Methylmorphine
ture and biologic activity were conducted by Crum-Brown (analgesic) (muscle relaxant)
and Fraser (1) in 1869. They demonstrated that many
compounds containing tertiary amine groups exhibited
activity as muscle relaxants when converted to quaternary
ammonium compounds. Molecules with widely differing N N
X

pharmacologic properties, such as strychnine (a convul- CH3 H3C CH3

N N
sant), morphine (an analgesic), nicotine (a deterrent,
insecticide), and atropine (an anticholinergic), could
Nicotine N-Methylnicotine
be converted to muscle relaxants with properties simi- (insecticide) (muscle relaxant)
lar to those of tubocurarine when methylated (Fig. 2.1).
Crum-Brown and Fraser therefore concluded that mus-
cle relaxant activity required the presence of a quater- H3C H3C CH3
nary ammonium group within the structure. This initial N N X
hypothesis was later disproven by the discovery of the natu-
ral neurotransmitter and activator of muscle contraction, H H
CH2OH CH2OH
acetylcholine (Fig. 2.2). Even though Crum-Brown and O O
Fraser’s initial hypothesis that related chemical structure
with action as a muscle relaxant was incorrect, it demon- O O

strated the concept that molecular structure influences N-Methylatropine

Atropine
the biologic activity of chemical entities and that altera- (mydriatic) (muscle relaxant)
tions in structure produce changes in biologic action.
With the discovery by Crum-Brown and Fraser that FIGURE 2.1 Effects of methylation on biologic activity.
quaternary ammonium groups could produce molecules
with muscle relaxant properties, scientists began to look
for other functional groups that produce specific bio- exerted their effects was still a mystery. Using his obser-
logic responses. At this time, it was thought that specific vations with regard to the staining behavior of micro-
chemical groups, or nuclei (rings), were responsible for organisms, Ehrlich (4) developed the concept of drug
specific biologic effects. This led to the postulate, that receptors. He postulated that certain “side chains” on the
took some time to disprove, that “one chemical group surfaces of cells were “complementary” to the dyes (or
gives one biological action” (2). Even after the discovery drug) and suggested that the two could therefore inter-
of acetylcholine by Loewi and Navrati (3), which effec- act with one another. In the case of antimicrobial com-
tively dispensed with Crum-Brown and Fraser’s concept pounds, interaction of the chemical with the cell surface
of all quaternary ammonium compounds being muscle “side chains” produced a toxic effect. This concept was
relaxants, this was still considered to be dogma and took the first description of what later became known as the
a long time to refute. receptor hypothesis for explaining the biologic action
of chemical entities. Ehrlich also discussed selectivity
SELECTIVITY OF DRUG ACTION AND DRUG
RECEPTORS O CH3
N
Although the structures of many drugs or xenobiotics, or H3C O CH3
CH3
at least their functional group composition, were known
at the start of the 20th century, how these compounds
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FIGURE 2.2 Acetylcholine, a neurotransmitter and muscle relaxant.

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 31

of drug action via the concept of a “magic bullet.” He action. One need only peruse the structures of drug
suggested that this selectivity permitted eradication of molecules in a particular pharmacologic class to become
disease states without significant harm coming to the convinced (e.g., histamine H1 antagonists, histamine H2
organism being treated (i.e., the patient). This was later antagonists, b-adrenergic antagonists). In the quest for
modified by Albert (5) and today is referred to as “selec- better medicinal agents (drugs), it must be determined
tive toxicity.” An example of poor selectivity was demon- which functional groups within a specific structure are
strated when Ehrlich developed organic arsenicals that important for its pharmacologic activity and how these
were toxic to trypanosomes as a result of their irrevers- groups can be modified to produce more potent, more
ible reaction with thiol groups (-SH) on vital proteins. selective, and safer compounds.
The formation of As–S bonds resulted in death to the An example of how different functional groups can
target organism. Unfortunately these compounds were yield chemical entities with similar physicochemical
toxic not only to the target organism, but also to the host properties is demonstrated by the sulfanilamide antibi-
once certain blood levels of arsenic were achieved. otics. In Figure 2.3, the structures of sulfanilamide and
The “paradox” that resulted after the discovery of p-aminobenzoic acid (PABA) are shown. In 1940, Woods
acetylcholine—how one chemical group can produce (7) demonstrated that PABA reverses the antibacterial
two different biologic effects (i.e., muscle relaxation and action of sulfanilamide (and other sulfonamide-based
muscle contraction)—was explained by Ing (6) using the antibacterials) and that both PABA and sulfanilamide
actions of acetylcholine and tubocurarine as his examples have similar steric and electronic properties. Both mol-
(see also Chapter 9). Ing hypothesized that both acetyl- ecules contain acidic functional groups, with PABA con-
choline and tubocurarine act at the same receptor, but taining an aromatic carboxylic acid and sulfanilamide an
that one molecule fits to the receptor in a more comple- aromatic sulfonamide. When ionized at physiologic pH,
mentary manner and “activates” it, causing muscle con- both compounds have a similar electronic configuration,
traction. (Ing did not elaborate just how this activation and the distance between the ionized acid and the weakly
occurred.) The blocking effect of the larger molecule, basic amino group is also very similar. It should be no
tubocurarine, could be explained by its occupation of surprise that sulfanilamide acts as an antagonist to PABA
part of the receptor, thereby preventing acetylcholine, metabolism in bacteria.
the smaller molecule, from interacting with the receptor.
With both molecules, the quaternary ammonium func- Biologic Targets for Drug Action
tional group is a common structural feature and inter- In order for drug molecules to exhibit their pharmaco-
acts with the same region of the receptor. If one closely logic activity, they must interact with a biologic target,
examines the structures of other molecules with opposing typically a receptor, enzyme, nucleic acid, or excitable
effects on the same pharmacologic system, this appears to membrane or other biopolymer. These interactions
be a common theme: Molecules that block the effects of occur between the functional groups found in the drug
natural neurotransmitters, such as norepinephrine, his- molecule and those found within each biologic target.
tamine, dopamine, or serotonin for example are called The relative fit of each drug molecule with its target is
antagonists and, are usually larger in size than the native a function of a number of physicochemical properties
compound, which is not the case for antagonists of pep- including acid–base chemistry and related ionization,
tide neurotransmitters and hormones such as cholecysto- functional group shape and size, and three-dimensional
kinin, melanocortin, or substance P. Antagonists to these spatial orientation. The quality of this “fit” has a direct
peptide molecules are usually smaller in size. However, impact on the biologic response produced. In this
regardless of the type of neurotransmitter (biogenic chapter, functional group characteristics are discussed
amine or peptide), both agonists and antagonists share as a means to better understand overall drug molecule
common structural features with the neurotransmitter absorption, distribution, metabolism, and excretion, as
that they influence. This provides support to the con- well as potential interaction with a biologic target.
cept that the structure of a molecule, its composition and
arrangement of functional groups, determines the type
of pharmacologic effect that it possesses (i.e., SAR). For H H H H
example, compounds that are muscle relaxants that act N N

via the cholinergic nervous system possess a quaternary 6.7 A 6.9 A

ammonium or protonated tertiary ammonium group and
are larger than acetylcholine (compare acetylcholine in C O S O
Fig. 2.2 with tubocurarine in Fig. 2.1). O O
N
SARs are the underlying principle of medicinal chem- H
p-Aminobenzoic acid Sulfanilamide
istry. Similar molecules exert similar biologic actions in a
qualitative sense. A corollary to this is that structural ele- FIGURE 2.3 Ionized forms of p-aminobenzoic acid (PABA) and
ments (functional groups) within a molecule most often sulfanilamide, with comparison of the distance between amine and
contribute in an additive manner to the physicochemical ionized acids of each compound. Note how closely sulfanilamide
properties of a molecule and, therefore, to its biologic resembles PABA.
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 32 PART I / PRINCIPLES OF DRUG DISCOVERY

PHYSICOCHEMICAL PROPERTIES OF DRUGS halogen ketone, neutral

neutral
Acid–Base Properties O
F CO2H carboxylic acid
The human body is 70 to 75% water, which amounts to aryl amine
weak base
approximately 51 to 55 L of water for a 160-lb (73-kg) N N
aryl amine, weak base
individual. For an average drug molecule with a molecu- HN

lar weight of 200 g/mol and a dose of 20 mg, this leads alkyl amine
to a solution concentration of approximately 2 × 10−6 basic
M (2 mM). When considering the solution behavior
FIGURE 2.4 Chemical structure of ciprofloxacin showing the vari-
of a drug within the body, we are dealing with a dilute
ous organic functional groups.
solution, for which the Brönsted-Lowry (8) acid–base
theory is most appropriate to explain and predict
acid–base behavior. This is a very important concept
in medicinal chemistry, because the acid–base proper- neutral functional groups are shown in Table 2.3.
ties of drug molecules have a direct effect on absorp- Quaternary ammonium compounds are neither acidic
tion, excretion, and compatibility with other drugs in nor basic and are not electrically neutral. Additional
solution. According to the Brönsted-Lowry Theory, an information about the acid–base properties of the func-
“acid” is any substance capable of yielding a proton tional groups listed in Tables 2.1 through 2.3 can be
(H+), and a “base” is any substance capable of accepting found in Gennaro (9) and Lemke (10). Review of func-
a proton. When an acid gives up a proton to a base, it is tional groups and their acid–base properties can also
converted to its “conjugate base.” Similarly, when a base be found at www.duq.edu/pharmacy/faculty/harrold/
accepts a proton, it is converted to its “conjugate acid” basic-concepts-in-medicinal-chemistry.cfm.
(Eqs. 2.1 and 2.2): A molecule can contain multiple functional groups
with acid–base properties and, therefore, can possess
CH3COOH + H2O ! CH3COOΘ + H3O⊕ both acidic and basic character. For example, ciproflox-
Acid Base Conjugate Conjugate acin (Fig. 2.4), a fluoroquinolone antibacterial agent,
Eq. 2.1 contains a secondary alkylamine, two tertiary arylamines
(acetic acid) (water) Base Acid
(acetate) (hydronium ion) (aniline-like amines), and a carboxylic acid. The two aryl-
amines are weakly basic and, therefore, do not contribute
CH3 NH2 + H2O ! CH3 NH3⊕ + ΘOH significantly to the acid–base properties of ciprofloxacin
Eq. 2.2 Base Acid Conjugate Conjugate under physiologic conditions. Depending on the pH of
(methylamine) (water) Acid Base the physiologic environment, this molecule will either
(methylammionium ion) (hydroxide ion) accept a proton (secondary alkylamine), donate a proton
(carboxylic acid), or both. Thus, it is described as ampho-
Note that when an acidic functional group loses its
teric (both acidic and basic) in nature. Figure 2.5 shows
proton (often referred to as having undergone “dissocia-
the acid–base behavior of ciprofloxacin in two different
tion”), it is left with an extra electron and becomes nega-
environments. Note that at a given pH (e.g., pH 1.0 to
tively charged. This is the “ionized” form of the acid. The
3.5), only one of the functional groups (the alkylamine)
ability of the ionized functional group to participate in an
is significantly ionized. To be able to make this predic-
ion-dipole interaction with water (see the Water Solubility
tion, an appreciation for the relative acid–base strength
of Drugs section) enhances its water solubility. Many
of both the acidic and basic functional groups is required.
functional groups behave as acids (Table 2.1). The ability
Thus, one needs to know which acidic or basic functional
to recognize these functional groups and their relative
group within a molecule containing multiple functional
acid strengths helps to predict absorption, distribution,
groups is the strongest and which acidic or basic func-
excretion, and potential incompatibilities between drugs.
tional group is the weakest. The concept of pKa not only
When a basic functional group is converted to the
describes relative acid–base strength of functional groups,
corresponding conjugate acid, it too becomes ionized.
In this instance, however, the functional group becomes
positively charged due to the extra proton. Most drugs
O
that contain basic functional groups contain primary, O
F COO
F CO2H
secondary, and tertiary amines or imino amines, such
as guanidines and amidines. Other functional groups N N N N
that are basic are shown in Table 2.2. As with the acidic H N H N
groups, it is important to become familiar with these H H

functional groups and their relative strengths. Colon (pH 5.6–7)

Stomach (pH 1.0–3.5)
Functional groups that cannot give up or accept a pro-
ton are considered to be “neutral” (or “nonelectrolytes”) FIGURE 2.5 Predominate forms of ciprofloxacin at two different
with respect to their acid–base properties. Common locations within the gastrointestinal tract.

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 33

TABLE 2.1
..ccoomm
Common Acidic Organic Functional Groups and Their Ionized (Conjugate Base) Forms
Acids (pKa)

u
u s
s e
e Conjugate Base

Phenol (9-11)

KKaadd R
OH

R
O
Phenolate

Sulfonamide (9-10)

ww.. O O Sulfonamidate

wwww
R S NH2 R S NH
O O

Imide (9-10) O O O O O O
Imidate
R N R' R N R'
H R N R'

Alkylthiol (10-11) R–SH Thiolate

R S

Thiophenol (9-10) SH Thiophenolate

S
R
R

N-Arylsulfonamide (6-7) O O N-Arylsulfonamidate

mm
H
R S N R S N

oo
O O

Sulfonimide (5-6)

ssee..cc O O O
R'

O O O
R'

O O O
Sulfonimidate

uu
S
R N R' S S

d
d
H R N R' R N R'

Alkylcarboxylic acid (5-6)

K
.. Kaa O
R C OH
O
R C O
Alkylcarboxylate

ww
wwww
Arylcarboxylic acid (4-5) COOH
COO
Arylcarboxylate
R
R

Sulfonic acid (0-1) O O O O Sulfonate

S S
R OH R O

Acid strength increases as one moves down the table.

but also allows one to calculate, for a given pH, the rela- Eq. 2.3 HCl + H2O ! ClΘ + H3O⊕
tive percentages of the ionized and un-ionized forms of

mm
the drug. As stated earlier, this helps to predict relative

o
o
water solubility, absorption, and excretion for a given Eq. 2.4 NaOH + H2O ! Na ⊕ + OHΘ + H2O
compound.

Relative Acid Strength (pKa)

ssee..cc Acids and bases of intermediate or weak strength,
however, incompletely donate (dissociate) or accept a

u
u
proton, and the equilibrium between the ionized and

K K add
Strong acids and bases completely donate (dissociate)

a
or accept a proton in aqueous solution to produce their
un-ionized forms lies somewhere in the middle, such
that all possible species can exist at any given time. Note

..
respective conjugate bases and acids. For example, min- that in Equations 2.3 and 2.4, water acts as a base in
eral acids, such as hydrochloric acid (HCl), or bases, such one instance and as an acid in the other. Water is there-

ww
as sodium hydroxide (NaOH), undergo 100% dissocia- fore amphoteric—that is, it can act as an acid or a base,

wwww
tion in water, with the equilibrium between the ionized depending on the prevailing pH of the solution. From
and un-ionized forms shifted completely to the right a physiologic perspective, drug molecules are always
(ionized), as shown in Equations 2.3 and 2.4:
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 34 PART I / PRINCIPLES OF DRUG DISCOVERY

TABLE 2.2 Common Basic Organic Functional Groups and Their Ionized (Conjugate Acid) Forms
Base (pKa) Conjugate Acid

Arylamine NH2 Arylammonium

NH3
(9-11) R
R

Aromatic amine N NH Aromatic ammonium

(5-6) R R

Imine R C NH Iminium
H
(3-4) R C NH
H

Alkylamines NH Alkylammonium
(20 - 10-11) NH2
(10 - 9-10)
R NH2
R NH3

Amidine NH NH2 Amidinium

(10-11)
R NH2 R NH2

Guanidine NH Guanidinium
NH2
(12-13)
R N NH2
H R N NH2
H

that is present is OH−, and the strongest acid is H3O+. (Eq. 2.5). Therefore, under physiologic conditions, alco-
This is known as the “leveling effect” of water. Thus, hols are neutral with respect to acid–base properties:
some functional groups that have acidic or basic charac-
ter do not behave as such under physiologic conditions Eq. 2.5 CH3CH2OH + H2 CH3CH2O– + H3O⊕
in aqueous solution. For example, alkyl alcohols, such
as ethyl alcohol, are not sufficiently acidic to become
significantly ionized in an aqueous solution at a physi- Predicting the Degree of Ionization of a Molecule
ologically pH. Water is not sufficiently basic to remove By knowing if there are acidic and/or basic func-
the proton from ethyl alcohol to form the ethoxide ion tional groups present in a molecule, one can predict

TABLE 2.3 Common Organic Functional Groups That are Considered Neutral Under Physiologic Conditions
R–CH2–OH O O O O
R R' S R'
R' R O
R O

Alkyl alcohol Ether Ester Sulfonic acid ester

O H R–C≡N R'
N
R N R"
R NH2
R'''
R R'

Amide Diarylamine Nitrile Quaternary ammonium

R' O S O O O
R R'
R N O S S
R R' R R' R R'
R"

Amine oxide Ketone & Aldehyde Thioether Sulfoxide Sulfone

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 35

whether a molecule is going to be predominantly ion-

ized or un-ionized at a given pH. To be able to quanti-
tatively predict the degree of ionization of a molecule, O O O O O O
the pKa values of each of the acidic and basic func-
tional groups present and the pH of the environ- HN NH HN N HN N

ment in which the molecule will be located must be O O O

known. The magnitude of the pKa value is a measure Acid form Conjugate base
of relative acid or base strength, and the Henderson- pKa 8.0
Hasselbalch equation (Eq. 2.6) can be used to calculate Question: At a pH of 7.4, what is the percent ionization of
the percent ionization of a compound at a given pH amobarbital?
(this equation was used to calculate the major forms of
[acid]
ciprofloxacin in Fig. 2.5): Answer: 8.0 = 7.4 + log
[base]

[acid form] 0.6 = log

[acid]
Eq. 2.6 pK a = pH + log [base]
[base form]

The key to understanding the use of the Henderson- 10 0.6 =

[acid] 3.98
=
Hasselbalch equation for calculating percent ionization [base] 1
is to realize that this equation relates a constant, pKa, to
the ratio of the acidic form of a functional group to its % acid form = 3.98 x 100 = 79.9%
4.98
conjugate base form (and conversely, the conjugate acid
form to its base). Because pKa is a constant for any given FIGURE 2.6 Calculation of percent ionization of amobarbital.
functional group, the ratio of acid to conjugate base (or Calculation indicates that 80% of the molecules are in the acid
conjugate acid to base) will determine the pH of the solu- (or protonated) form, leaving 20% in the conjugate base (ionized)
tion. A sample calculation is shown in Figure 2.6 for the form.
sedative hypnotic amobarbital.
When dealing with a basic functional group, one
must recognize the conjugate acid represents the ion-
ized form of the functional group. Figure 2.7 shows as a result of an unequal sharing of electrons between
the calculated percent ionization for the decongestant the two atoms within a covalent bond. This unequal shar-
phenylpropanolamine. It is very important to under- ing of electrons only occurs when these two atoms have
stand that for a base, the pKa refers to the conjugate significantly different electronegativities. When a per-
acid or ionized form of the compound. To thoroughly manent dipole is present, a partial charge is associated
comprehend this relationship, calculate the percent
ionization of an acidic functional group and a basic
functional group at different pH values and carefully
observe the trend. OH OH
NH2 NH3
CH3
Water Solubility of Drugs CH3

The solubility of a drug molecule in water greatly affects

the routes of administration that are available, as well as Base form Conjugate acid form
its absorption, distribution, and elimination. Two key pKa 9.4
concepts to keep in mind when considering the water (or Question: What is the % ionization of phenylpropanolamine at
fat) solubility of a molecule are the potential for hydro- pH 7.4?
gen bond formation and ionization of one or more func- [acid]
Answer: 9.4 = 7.4 + log
tional groups within the molecule. [base]
[acid]
2.0 = log
Hydrogen Bonds [base]
Each functional group capable of donating or accepting
a hydrogen bond contributes to the overall water solu- [acid] 100
102 = =
bility of the compound and increases the hydrophilic [base] 1
(water-loving) nature of the molecule. Conversely, func-
tional groups that cannot form hydrogen bonds do not % ionization = 100 x 100 = 99%
101
enhance hydrophilicity and will contribute to the hydro-
phobic (water-fearing) nature of the molecule. Hydrogen FIGURE 2.7 Calculation of percent ionization of phenylpropanol-
bonds are a special case of what are usually referred to as amine. Calculation indicates that 99% of the molecules are in the
dipole–dipole interactions. A permanent dipole occurs acid form, which is the same as the percent ionization.
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 36 PART I / PRINCIPLES OF DRUG DISCOVERY

ACID–BASE CHEMISTRY/COMPATIBILITY
ABSORPTION/ACID–BASE CASE CASES
A long-distance truck driver comes into the pharmacy com- The intravenous (IV) technician in the hospital pharmacy gets
plaining of seasonal allergies. He asks you to recommend an an order for a patient that includes the two drugs drawn below.
agent that will act as an antihistamine but that will not cause She is unsure if she can mix the two drugs together in the same IV
drowsiness. He regularly takes TUMS for indigestion due to the bag and is not certain how water soluble the agents are.
bad food that he eats while on the road.
H3C
Cl O
H N H3PO4
Cl O C N H H
S CH3
H2PO4
N CH3 CH3O
O COOH CH3
CH N N O O
O CO2 K
N
OH
H CH3
Penicillin V Potassium Codine phosphate
Cetirizine (Zyrtec) Clemastine (Tavist)

O
1. Penicillin V potassium is drawn in its salt form, whereas
codeine phosphate is not. Modify the structure above to
COOH
show the salt form of codeine phosphate. Determine the
acid–base character of the functional groups in the two
N CH3
molecules drawn above as well as the salt form of codeine
CH3
phosphate.
Olopatadine (Patanol) 2. As originally drawn above, which of these two agents is
more water soluble? Provide a rationale for your selection
1. Identify the functional groups present in Zyrtec and Tavist, that includes appropriate structural properties. Is the salt
and evaluate the effect of each functional group on the form of codeine phosphate more or less water soluble than
ability of the drug to cross lipophilic membranes (e.g., the free base form of the drug? Provide a rationale for your
blood–brain barrier). Based on your assessment of each answer based on the structural properties of the salt form
agent’s ability to cross the blood–brain barrier (and, there- of codeine phosphate.
fore, potentially cause drowsiness), provide a rationale for 3. What is the chemical consequence of mixing aqueous solu-
whether the truck driver should be taking Zyrtec or Tavist. tions of each drug in the same IV bag? Provide a rationale
2. Patanol is sold as an aqueous solution of the hydrochloride that includes an acid–base assessment.
salt. Modify the structure present in the box to show the
appropriate salt form of this agent. This agent is applied
to the eye to relieve itching associated with allergies.
Describe why this agent is soluble in water and what prop- Thus, for a hydrogen bonding interaction to occur, at
erties make it able to be absorbed into the membranes that least one functional group must contain a dipole with
surround the eye. an electropositive hydrogen. The hydrogen atom must
3. Consider the structural features of Zyrtec and Tavist. be covalently bound to an electronegative atom, such as
In which compartment (stomach [pH 1] or intestine oxygen (O), nitrogen (N), sulfur (S), or selenium (Se).
[pH 6 to 7]) will each of these two drugs be best absorbed?
Of these four elements, only oxygen and nitrogen atoms
4. TUMS neutralizes stomach acid to pH 3.5. Based on your
contribute significantly to the dipole, and we will there-
answer to question 3, determine whether the truck driver
fore concern ourselves only with the hydrogen-bonding
will get the full antihistaminergic effect if he takes his
antihistamine at the same time that he takes his TUMS.
capability (specifically as hydrogen bond donors) of func-
Provide a rationale for your answer. tional groups that contain a bond between oxygen and
hydrogen atoms (e.g., alcohols) and functional groups
that contain a bond between nitrogen and hydrogen
atoms (e.g., primary and secondary amines and amides)
with each of these atoms along a single bond (one atom (e.g., NH and CONH groups).
has a partial negative charge, and one atom has a partial Even though the energy associated with each hydro-
positive charge). The atom with a partial negative charge gen bond is small (1 to 10 kcal/mol/bond), it is the addi-
has higher electron density than the other atom. When tive nature of multiple hydrogen bonds that contributes
two functional groups that contain one or more per- to the overall water solubility of a given drug molecule.
manent dipoles approach one another, they align such This type of interaction is also important in the interac-
that the negative end of one dipole is electrostatically tion between a drug and its biologic target (e.g., recep-
attracted to the positive end of the other. When the posi- tor). Figure 2.8 shows several types of hydrogen bonding
tive end of the dipole is a hydrogen atom, this interac- interactions that can occur with a couple of functional
tion is referred to as a “hydrogen bond” (or H-bond).
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groups and water. As a general rule, the more hydrogen

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 37

H H
O H
O H H δ+
H H
H O O −
H H δ O δ+ δ−
N H O H
H O
H H+ δ+
O N δ
R R' O
HH
H O H

FIGURE 2.8 Examples of hydrogen bonding between water and FIGURE 2.9 Examples of ion–dipole interactions.
hypothetical drug molecules.

bonds that are possible between a drug molecule and the partially positively charged atom found in a perma-
water, the greater the water solubility of the molecule. nent dipole (e.g., the hydrogen atoms in water) (Fig. 2.9).
Table 2.4 lists several common functional groups and Organic salts are composed of a drug molecule in
the number of hydrogen bonds in which they can poten- its ionized form and an oppositely charged counterion.
tially participate. Note that this table does not take into For example, the salt of a carboxylic acid is composed
account the possibility of intramolecular hydrogen of the carboxylate anion (ionized form of the functional
bond formation. Each intramolecular hydrogen bond group) and a positively charged ion (e.g., Na+) and the
decreases water solubility (and increases lipid solubility) salt of a secondary amine is composed of the ammonium
because there is one less interaction possible with water. cation (ionized form of the functional group and a nega-
tively charged ion; e.g., Cl−). Not all organic salts are very
Ionization water soluble. To associate with enough water molecules
In addition to the hydrogen-bonding capacity of a mole- to become soluble, the salt must be highly dissociable; in
cule, another type of interaction plays an important role in other words, the cation and anion must be able to sepa-
determining water solubility: the ion–dipole interaction. rate and interact independently with water molecules.
This type of interaction can occur with organic salts. Ion– Highly dissociable salts are those formed from strong
dipole interactions occur between either a cation and the acids with strong bases (e.g., sodium chloride), weak acids
partially negatively charged atom found in a permanent with strong bases (e.g., sodium phenobarbital), or strong
dipole (e.g., the oxygen atom in water) or an anion and acids with weak bases (e.g., atropine sulfate). Examples
of strong acids (strong acids are 100% ionized in water
[i.e., no ionization constants or pKa values of <1]) include
the hydrohalic (hydrochloric, hydrobromic, and hydro-
ABSORPTION/BINDING INTERACTIONS fluoric), sulfuric, nitric, and perchloric acids. All other
CASE acids (e.g., phosphoric, tartaric, acetic, and other organic
acids, and phenols) are partially ionized with pKa values
A 24-year-old man comes into the pharmacy and asks you to from 1 to 14 and are, therefore, considered to be moder-
recommend a treatment for the itching and burning he has ate or weak acids. Hydroxides of sodium, potassium, and
recently noticed on both feet. He indicates that he would prefer
a cream rather than a spray or a powder. Your recommenda-
tion to this patient is to use Lamisil (terbinafine), a very effec- TABLE 2.4 Common Organic Functional Groups and
tive topical antifungal agent that is sold over the counter. Their Hydrogen-Bonding Potential

CH3 Functional Groups Number of Potential H-bonds

N
R–OH 3

O 2
R R'
Terbinafine (Lamisil)
R–NH2 3

1. Identify the structural characteristics and the correspond- R NH 2

ing properties that make terbinafine an agent that can be R'
used topically.
2. The biologic target of drug action for terbinafine is squa- R N R" 1
lene epoxidase. Consider each of the structural features of R'
this antifungal agent and describe the type of interactions
that the drug will have with the target for drug action. O 2
Which amino acids are likely to be present in the active site R'
R O
of this enzyme?

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 38 PART I / PRINCIPLES OF DRUG DISCOVERY

calcium are strong bases because they are 100% ionized, Carboxylic acid
whereas other bases, such as amines, are of moderate or COOH
weak strength. The salt formed by a carboxylic acid with
NH2
an alkylamine is the salt of a weak acid and weak base, HO
respectively. This salt does not dissociate appreciably and Phenol
Primary alkyl amine
cannot significantly contribute to the overall water solu-
bility of a given drug molecule. In general, low molecular FIGURE 2.11 Organic functional groups in tyrosine (see text for
weight salts are water soluble, and high molecular weight pKa values).
salts are water insoluble. Examples of common organic
salts used in pharmaceutical preparations are provided
in Figure 2.10. only 0.45 g/1,000 mL. The basic alkylamine (pKa 9.1 for
The extent to which ionized molecules are soluble the conjugate acid) and the carboxylic acid (pKa 2.2)
in water is also dependent on the presence of intramo- are both ionized at physiologic pH, and a zwitterionic
lecular ionic interactions. Molecules with ionizable func- molecule results. These two charged groups are suffi-
tional groups of opposite charges have the potential to ciently close that a strong ion–ion interaction occurs,
interact with each other rather than with water mole- thereby keeping each group from participating in
cules. When this occurs, these molecules often become ion–dipole interactions with surrounding water mol-
water insoluble. A classic example is the amino acid ecules. This lack of interaction between the ions and
tyrosine (Fig. 2.11). Tyrosine contains three very polar the dipoles found in water results in a molecule that is
functional groups, two of which are ionizable (the alkyl- very water insoluble (Fig. 2.12). Not all zwitterions or
amine and carboxylic acid) depending on the pH of the multiply charged molecules demonstrate this behavior;
environment. only those that contain ionized functional groups close
The phenolic hydroxyl group is also ionizable (pKa enough for an ionic interaction to occur will be poorly
9 to 10); however, it does not contribute significantly soluble. Generally, the greater the separation between
to the ionization of tyrosine under pharmaceutically or charges, the more highly water soluble one anticipates
physiologically relevant conditions (<1% ionized at pH 7). the molecule will be. This is only true, however, up to a
Because of the presence of three very polar functional certain number of carbon atoms. This will be discussed
groups (two of them being ionizable), one would expect in more detail later.
tyrosine to be very soluble in water, yet its solubility is
Predicting Water Solubility: The Empirical
HO HO
Approach
Lemke (10) developed an empiric approach to predict-
O O
ing the water solubility of molecules based on the carbon-
N
H
N
H
OOC OH solubilizing potential of several functional groups. In his
Cl
COOH
approach, if the solubilizing potential of the functional
N N OH groups exceeds the total number of carbon atoms pres-
ent, then the molecule is considered to be water solu-
Cl Cl ble. Otherwise, it is considered to be water insoluble.
Participation in intramolecular hydrogen bonding or
Hydroxyzine hydrochloride Hydroxyzine pamoate ionic interactions decreases the solubilizing potential of
(1g/mL) (1g/1000 mL)
a given functional group. It is difficult to quantitate how
N much such interactions will decrease a molecule’s overall
O H
H
N S CH3
H
O N S CH3 water solubility.
O N O N CH3 Table 2.5 shows the water-solubilizing potential for
CH3 O
O
COO COO several functional groups common to many drugs.
NH2 Na Because most drug molecules contain more than one
Penicillin G procaine Penicillin G sodium functional group (i.e., are polyfunctional), the second
(1g/40 mL)
(1g/250 mL) column in the table will be of more utility. To demon-
strate Lemke’s method, consider the structure of anile-
H3C
H3C
O N H
ridine. Anileridine (Fig. 2.13) is an opioid analgesic that
O N H OH CH3 SO4-2 contains three functional groups that contribute to water
CH3 OOC CH3NH O N
CH3NH O N
CH3
CH3
2

Physostigmine salicylate Physostigmine sulfate COO

(1g/75 mL) (1g/4 mL)
NH3
HO
FIGURE 2.10 Water solubilities of different salt forms of selective
drugs.
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FIGURE 2.12 Zwitterionic form of tyrosine showing ion–ion bond.

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 39

BINDING INTERACTIONS CASE WATER/LIPID SOLUBILITY CASE

Each of these drug molecules interacts with a different biologic When you look at any drug molecule, there are a number of
target and elicits a unique pharmacologic response. For each functional groups present that contribute to the properties of
of the three molecules, list the types of interactions that are that drug molecule. Identify the types of functional groups in
possible with a biologic target. For each type of interaction, each molecule and to which physical properties (water/lipid
provide one example of an amino acid that could participate in solubility) each contributes.
that interaction.
1. Structural feature Physical property

CH3
O N
H
OH
N N

O
Cl

Betaxolol (Betoptic)
Meclizine (Antivert)
O O
C OCH3
H3C OH 2. Structural feature Physical property
HO
CF3
Misoprostol (Cytotec)

O
OH S NH
H H CH3
N
HO O

HO Fluoxetine (Prozac)
Salmeterol (Serevent)

Example: Binding interaction: Van der Waals 3. Structural feature Physical property
Amino acid: Leucine CH3
H3C CH3
OH
CH3
solubility: an aromatic amine (very weak base), a tertiary
alkylamine (weak base), and an ester (neutral). There
are a total of 21 carbon atoms in the molecule and a
solubilizing potential from the three functional groups CH2

of nine carbon atoms. Since the solubilizing potential of HO OH

the functional groups is less than the total number of
carbons that are present, it is predicted that anileridine 1,25-Dihydroxy Vit D2
is insoluble in water. This is, indeed, the case: The solu-
bility of anileridine is reported in the U.S. Pharmacopeia
(USP) as 1 g/10,000 mL, or 0.01%. Now consider the
hydrochloride salt of anileridine. Not only do the three
functional groups contribute a solubilizing potential of
Tertiary alkylamine, 3 carbons nine carbon atoms, the positive charge of the alkylammo-
N nium contributes also to its water solubility. Lemke (10)
CO2CH2CH3 Ester, 3 carbons estimates that each ionized functional group (cationic
H2N or anionic) found within a drug molecule contributes
Aromatic or a solubilizing potential of 20 to 30 carbon atoms. Thus,
arylamine, the solubilizing potential for all of the functional groups
3 carbons in anileridine hydrochloride is 29 to 39 carbon atoms,
which is more than the total number of carbon atoms
Anileridine
in the molecule. This salt should therefore be soluble
FIGURE 2.13 Identification of functional groups in anileridine.
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in water, and it is (to the extent of 0.2 g/mL, or 20%).

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 40 PART I / PRINCIPLES OF DRUG DISCOVERY

TABLE 2.5 Water-solubilizing Potential of Organic

INTERACTIONS/SOLUBILITY CASE Functional Groups in a Mono- or Polyfunctional
Molecule
J.K. presents a prescription for her 6-month-old daughter for Functional Monofunction Polyfunctional
Donatussin Drops. She wants to know if this medication will Group Molecule Molecule
have an effect on her daughter’s alertness.
Alcohol 5 to 6 carbons 3 to 4 carbons
Components of Donatussin:
Phenylephrine (decongestant) Phenol 6 to 7 carbons 3 to 4 carbons
Chlorpheniramine (antihistamine)
Guaifenesin (expectorant) Ether 4 to 5 carbons 2 carbons

Aldehyde 4 to 5 carbons 2 carbons

OH N CH3
HO NHCH3
N Ketone 5 to 6 carbons 2 carbons
CH3
Amine 6 to 7 carbons 3 carbons

Carboxylic acid 5 to 6 carbons 3 carbons

Phenylephrine
Cl
Ester 6 carbons 3 carbons
OH Chlorpheniramine
OCH3 Amide 6 carbons 2 to 3 carbons
O
OH
Urea, carbonate, 2 carbons
carbamate
Guaifenesin
Water solubility is defined as greater than 1% solubility (9).

1. Identify the structural features/functional groups of phenyl-

ephrine and guaifenesin that contribute to improved water
solubility (medication given as drops). List the type(s) of the hydrophobic or hydrophilic properties of each func-
interactions that these groups have with water, and draw tional group present in the molecule. Before we can cal-
an example of these interactions (with appropriate labels). culate logP values, a brief explanation of the concept of
2. Evaluate each of the three molecules, and determine if partition coefficient is necessary.
each molecule contains any functional groups that will
allow the drug to cross the blood–brain barrier and have an Eq. 2.7 P = Coct /C water
effect on this child’s alertness (create a list of relevant func-
tional groups for each molecule). Based on your evaluation, In its simplest form, the partition coefficient, P, refers
which agent is likely to have the most significant effect? to the ratio of drug concentration in octanol (Coct) to that
Identify what property is necessary for these agents to in water (Cwater) (Eq. 2.7). Octanol is used to mimic the
cross this biologic membrane. amphiphilic nature of lipid, because it has a polar head
3. Identify the binding interactions that chlorpheniramine group (primary alcohol) and a long hydrocarbon chain,
and guaifenesin could have with their respective targets or tail, similar to the fatty acid tail that makes up part of
for drug action. Be sure to identify which functional groups a lipid membrane. Because P is logarithmically related to
will participate in each of these binding interactions. free energy (12), P is generally expressed as logP and is,
therefore, the sum of the hydrophobic and hydrophilic
characteristics of the functional groups that make up the
structure of the molecule. Thus, logP is a measure of the
Problem 6, found at the end of the chapter, provides an lipid/water solubility characteristics of the entire molecule.
additional opportunity to use this approach to predict Because each functional group contained within the mol-
water solubility. Solubility data for these drug molecules ecule contributes to the overall hydrophilic/hydrophobic
can be found in the USP. In most instances, discrepan- character of the molecule, a hydrophilic/hydrophobic
cies between approximate and actual water solubilities value (the hydrophobic substituent constant, p) can be
can be rationalized by careful inspection of the chemical assigned to each functional group. Equation 2.8 defines
structure. this relationship:

Predicting Water Solubility: Analytical/Quantitative Eq. 2.8 LogP = Σπ (fragments)

Approach
Another method for predicting water solubility involves When calculating logP from hydrophobic substituent
calculation of an approximate logP, or log of the parti- constants, the sum is usually referred to as logPcalc or
tion coefficient for a molecule. This approach is based ClogP [for software sources to calculate ClogP, see (16)]
on an approximation method developed by Cates (11) to distinguish it from an experimentally determined
and discussed in Lemke (10). In this approach, one sums
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value (MlogP or logPmeas). Over the years, extensive tables

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 41

of p values have been compiled for organic functional TABLE 2.6 Hydrophilic-lipophilic Values (pV) for
groups and molecular fragments (12–15). Table 2.6 is a Organic Fragments (10)
highly abbreviated summary of p values from Lemke (10),
based largely on the manuscript by Cates (11). Using the Functional Group p value p value
values in this table, a fairly reasonable estimate for the (aliphatic) (aromatic)
water solubility of many organic compounds (shown as H 0.00
logP) can be determined.
Again we will consider the structure of the opioid Alkane 0.50 0.56 (CH3);
analgesic anileridine to demonstrate the calculation 1.02 (CH2CH3)
of logP (Fig. 2.13). This compound has a total of 22 Alkene 0.82
carbon atoms, some aliphatic and some aromatic. We
C6H5 (phenyl) 2.15 1.96
need to distinguish between the aliphatic and aromatic
carbon atoms because the delocalized p orbitals for Br, Cl, F, I 0.60; 0.39; 0.86; 0.71;
the sp2 hybridized aromatic carbon atoms make them −0.17; 1.00 0.14; 1.12
more polar than aliphatic carbons. The compound also NO2 −0.85 −0.28
contains one tertiary alkylamine, one aromatic or aryl
amine, and one ester. Evaluation of esters and amides NH2 (primary amine) −1.19 −1.23
requires that the oxygen, nitrogen, and ester/amide car- NHR (secondary amine) −0.67 0.47
bon atoms are counted in this p value. The remaining
aliphatic carbons are then counted. Figure 2.14 summa- NR2 (tertiary amine) −0.30 0.18
rizes the logP calculation for anileridine. The calculation -NHC=OR (amide) −0.97
gives a ClogP value for anileridine of +4.8. Water solubil-
ity as defined by the USP is solubility greater than 3.3%, SC6H5 2.32
which equates to an approximate logP of +0.5. LogP val- OH −1.12 −0.67
ues less than +0.5 are therefore considered to be water
soluble, and those greater than +0.5 are considered to OCH3 −0.02
be water insoluble. According to our calculation, anile- -OC=OR (ester) −0.27 −0.64
ridine would be predicted to be insoluble in water. This
CHO (aldehyde) −0.65
calculation agrees with the more empiric procedure dis-
cussed earlier. C=OCH3 (ketone) −0.55
Other sample calculations are shown in Figure 2.15, and
CO2H −0.32
several problems are provided at the end of this chapter.
In Figure 2.15, MlogP values (when available) and ClogP SO2 NH2 (sulfonamide) −1.82
values (16) are included for comparison purposes (see
Appendix A for additional ClogP values). Even though the
p values from Table 2.6 are not as extensive as those in the
The ability to predict the percent ionization or water
computer program, there is good general agreement with
solubility of a molecule should not be viewed as an exer-
most of these compounds with respect to their solubility (or
cise in arithmetic, but rather as a way to understand the
insolubility) in water. In addition, other programs besides
solution behavior of molecules, especially as it relates to
ClogP are available to predict logP values; some of these
admixtures and the pharmacokinetic differences among
programs are available on the Internet. One must keep in
molecules. The ionization state of a molecule not only
mind that due to the assumptions made in these programs,
influences its water solubility, but also its ability to traverse
they cannot produce results that are in total agreement
with measured values or other prediction programs. ClogP
values calculated from ACDLogP (16) are generally more N
CO2CH2CH3
accurate. Other programs for calculating logP values, such
as Molinspiration (17) and Interactive Analysis (18), use H2N

different methods and assumptions and, therefore, do

not always agree with ClogP predictions or experimentally
determined values. This is not to say that the latter two pro- Fragments π
grams do not give accurate results. Often, one or all of the 1 primary alkylamine -1.23
programs will have reasonable agreement with measured 1 teriary alkylamine -0.30
values, but greater disagreement tends to occur as the 9 aliphatic carbons +4.5
number of functional groups in the molecule that partici- 2 phenyl rings +4.30
pate as hydrogen-bond acceptor and/or hydrogen-bond 1 ester -0.27
donor groups increases. This increases the likelihood that
logP +7.0
intramolecular interactions will occur—something that is
not always taken into account with these programs. FIGURE 2.14
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Calculation of logP for anileridine.

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 42 PART I / PRINCIPLES OF DRUG DISCOVERY

Fragments π Fragments π Fragments π

CH3 HO O +11.0
6 carbons +3.0 O 7 carbons +3.5 22 carbons
+2.15 1 sulfur 0.0 O O 1 alcohol -1.12
COOH 1 phenyl COOH
-0.64
1 carboxyl -0.32 HS N 1 carboxyl -0.32 2 carboxyls
CH3 -0.97 (CH2)2 O CH3
1 amide + 9.24
logP +4.83 H3C CH3 logP
Ibuprofen
logP +2.21
MlogP +3.5; ClogP +3.68 Captopril CH3 MlogP +4.26; ClogP +4.08
ClogP +1.16
Lovastatin
Fragments π Fragments π
H NH2
11 carbons +5.5 H 6 carbons +3.0
(CH3)3CN
1 phenyl +2.15 N S 1 phenyl +2.15
2 IMHB +1.3 O N 1 chloride +0.39
OH
1 secondary amine -0.67 O Cl 1 primary amine -1.19
O
1 ether -0.02 COOH 1 sulfur 0.0
3 alcohols -3.36 2 amides -1.94
1 carboxyl -0.32
HO logP +4.90 Cefaclor
logP +2.09
OH MlogP +0.71; ClogP +0.23
Nadolol MlogP -1.69; ClogP -1.79

FIGURE 2.15 ClogP calculations for selected compounds.

membranes and, therefore, its ability to be absorbed. The of these groups. This becomes an especially important
distribution of the drug and its ability to bind to proteins factor when the environment that a molecule is in is
other than its target are also greatly influenced by the asymmetric, such as the human body. Proteins and other
ionization state and the hydrophilic/hydrophobic nature biologic targets are asymmetric in nature. How a particu-
of the molecule. lar drug molecule interacts with these macromolecules is
determined by the three-dimensional orientation of the
functional groups present. If critical functional groups
in the drug molecule do not occupy the proper spatial
STEREOCHEMISTRY AND DRUG ACTION region, then productive interactions with the biologic
Stereoisomers are molecules that contain the same target will not be possible. As a result, it is possible that
number and kinds of atoms, the same arrangement of the desired pharmacologic activity will not be achieved.
bonds, but different three-dimensional structures; in If, however, the functional groups within a drug mol-
other words, they only differ in the three-dimensional ecule are located in the proper three-dimensional ori-
arrangement of atoms in space. There are two types entation, then the drug can participate in multiple key
of stereoisomers: enantiomers and diastereoisomers. interactions with its biologic target. It is important to
Enantiomers are pairs of molecules for which the understand not only which functional groups contrib-
three-dimensional arrangement of atoms represents ute to the pharmacologic activity of a drug, but also the
nonsuperimposable mirror images. Diastereoisomers importance of the three-dimensional nature of these
represent all of the other stereoisomeric compounds functional groups in predicting drug potency and poten-
that are not enantiomers. Thus, the term “diastereoiso- tial side effects.
mer” includes compounds that contain double bonds Approximately one in every four drugs currently on
(geometric isomers) and ring systems. Unlike enantio- the market is some type of isomeric mixture. For many
mers, diastereoisomers exhibit different physicochemi- of these drugs, the biologic activity can only reside in
cal properties, including, but not limited to, melting one isomer (or at least predominate in one isomer).
point, boiling point, solubility, and chromatographic The majority of these isomeric mixtures are termed
behavior. These differences in physicochemical proper- “racemic mixtures” (or “racemates”). A racemic mixture
ties allow the separation of individual diastereoisomers is comprised of equal amounts of both of the possible
from mixtures with the use of standard chemical sepa- drug enantiomers. As mentioned earlier in this chapter,
ration techniques, such as column chromatography or when enantiomers are introduced into an asymmetric,
crystallization. Enantiomers cannot be separated using or chiral, environment, such as the human body, they
such techniques unless a chiral environment is provided display different physicochemical properties. This can
or if they are first converted to diastereoisomers (e.g., lead to significant differences in their pharmacokinetic
salt formation with another enantiomer). Examples and pharmacodynamic behavior, resulting in adverse
of enantiomers and diastereoisomers are provided in side effects or toxicity. For example, the individual iso-
Figure 2.16. mers in a racemic mixture can exhibit significant differ-
The physicochemical properties of a drug molecule are ences in absorption (especially active transport), serum
dependent not only on what functional groups are pres- protein binding, and metabolism. As it relates to drug
ent in the molecule but also on the spatial arrangement
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metabolism, it is certainly possible that only one of the

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 43

ENANTIOMERS
CH3 H
QUESTIONS WE CAN NOW ANSWER
H H3C
ABOUT ANY DRUG MOLECULE
COO Na COO Na

CH3O CH3O Based on your knowledge of acid–base chemistry, from where

will this drug primarily be absorbed?
S-(+)-naproxen sodium R-(-)-naproxen sodium What is the solubility of the drug in the stomach, plasma, or
an aqueous IV?
H3C N N CH
3
What are the possible interactions that the drug could have
with its respective target for drug action?
What is the compatibility of the drug if mixed with other drugs?
How should this drug be delivered? Is it stable in stomach acid?
OH HO

Levorphanol (anagesic) Dextrorphan (antitussive) physical property of the molecule and does not describe
the absolute configuration or three-dimensional arrange-
DIASTEREOISOMERS ment of atoms around the chiral center.
In the late 19th century, Fisher and Rosanoff devel-
HO H HO H
NHCH3 NHCH3 oped a system of nomenclature based on the struc-
H CH3 ture of glyceraldehyde (Fig. 2.17). Since there were no
H
CH3 methods at that time to determine the absolute three-
dimensional arrangement of atoms in space, the two
1R, 2S-(-)-Ephedrine 1R, 2R-(-)-Pseudoephedrine isomers of glyceraldehyde were arbitrarily assigned
the designation of d-(+)- and l-(−). It was not until the
1950s that the absolute configurations of these mole-
N N
H cules were determined (Fisher had fortuitously guessed
N
N
correctly). The configurations of other molecules were
H
then assigned based on their relationship to d- or l-glyc-
eraldehyde via synthetic methods or chemical degrada-
H3 C H3C tion. Thus, via chemical degradation, it was possible
to determine that (+)-glucose, (−)-2–deoxyribose, and
Z-triprolidine (inactive) E-triprolidine (active) (−)-fructose had the same terminal configuration as
d-(+)-glyceraldehyde and, therefore, were assigned the
FIGURE 2.16 Examples of stereoisomers.
d-absolute configuration. Amino acid configurations
were assigned based on their relationship to d-(+)-
and l-(−)-serine (Fig. 2.17). Unfortunately, this system
isomers can be converted into a toxic substance or can becomes very cumbersome with molecules that contain
influence the metabolism of another drug (Chapter 4). more than one chiral center.
Since stereochemistry can have a profound effect on
both the pharmacokinetic and pharmacodynamic prop-
erties of a drug, it is important to review the founda- LEARNING THE LINGO: DRUG
tional concepts MOLECULE EVALUATION
Analysis of Individual Functional Groups:
Stereochemical Definitions
Name of functional group
Designation of Absolute Configuration Shape of functional group
At first, enantiomers were distinguished by their abil- Hydrophobic vs. hydrophilic character
ity to rotate the plane of polarized light. Isomers that Polar vs. nonpolar character
rotate the plane of polarized light to the right, or in a Acidic vs. basic (pKa) character
clockwise direction, were designated as dextrorotatory, Binding interactions
indicated by a (+)- sign before the chemical name [e.g., Chemical/enzymatic stability
(+)-amphetamine or dextroamphetamine]. The oppo- Analysis of the Whole Drug Molecule:
site designation, levorotatory or (−)-, was assigned to mol- Looking for functional group balance: water solubility and
ecules that rotate the plane of polarized light to the left, absorption
or in a counterclockwise direction. The letters d- and l- Ionization issues: effect on solubility and absorption
were formerly used to indicate (+)- and (−)-, respectively. Drug combinations: acid–base interactions
A racemate (racemic mixture)—that is, a 1:1 mixture of Drug interactions with biologic target: good fit or not?
enantiomers—is indicated by placement of a (±)- before Stability and bioavailability: route of administration
the compound name. This nomenclature is based on a
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 44 PART I / PRINCIPLES OF DRUG DISCOVERY

CHO CHO center results in the assignment of the S-absolute configura-

H OH HO H
tion for the more active enantiomer of propranolol. Close
CH2OH CH2OH
inspection of both R-norepinephrine and S-propranolol,
D-(+)-Glyceraldehyde L-(-)-Glyceraldehyde however, shows that the hydroxy group, basic amine, and
aromatic rings of both compounds occupy the same regions
COOH COOH in three-dimensional space.
H NH2 H2N H
CH2OH CH2OH

D-(+)-Serine L-(-)-Serine

FIGURE 2.17 Relationship of optical isomers of serine to D- and

L-glyceraldehyde.

Stereochemistry and Biologic Activity

In 1956, a new system of stereochemical nomenclature Easson-Stedman Hypothesis
was introduced by Cahn et al. (19) and is known as the In 1886, Piutti (20) reported different physiologic actions
Sequence Rule or CIP system. With this system, atoms for the enantiomers of asparagine, with (+)-asparagine
attached to a chiral center are ranked based on their having a sweet taste and (−)-asparagine a bland one. This
atomic number. Highest priority is given to the atom was one of the earliest observations that enantiomers can
with the highest atomic number, and subsequent atoms exhibit differences in biologic action. In 1933, Easson and
are ranked accordingly, from highest to lowest. When a Stedman (21) reasoned that differences in biologic activ-
decision cannot be made in the assignment of priority— ity between enantiomers resulted from selective reactivity
for example, two atoms with the same atomic number of one enantiomer with its receptor. They postulated that
attached to the chiral center—this evaluation extends to such interactions require a minimum of a three-point fit
the next atom until a priority can be established. When to the receptor. This is demonstrated in Figure 2.18 for
the molecule is then viewed from the side opposite to the two hypothetical enantiomers. In Figure 2.18, the letters
lowest-priority atom, the priority sequence from highest A, B, and C represent hypothetical functional groups that
to lowest can then be determined. If the priority sequence can interact with complementary sites on the hypotheti-
proceeds to the right, or in a clockwise direction, the chi- cal receptor surface, represented by A′, B′, and C′. Only
ral center is designated with an R-absolute configuration.
The designation is S when the priority sequence proceeds
to the left, or in a counterclockwise direction. An example
of this is seen in the neurotransmitter norepinephrine. D

A C
B

A C
B
Compound 6
Degradation studies demonstrate that (−)-norepi-
nephrine is related to d-(−)-mandelic acid; therefore,
it was given the d-designation using the Fisher system. A
With the CIP system, norepinephrine is assigned the
R-absolute configuration.
It should be noted that the CIP nomenclature system
uses a set of arbitrary rules and, therefore, should be viewed D C
as a system that tracks absolute configuration only. In many B
instances, two molecules can have different absolute con-
figurations as designated by the CIP system, but the same A C
relative orientation of the functional groups relevant for B
biologic activity. An example of this is demonstrated when
Compound 7
the absolute configuration of the nonselective b-adrenergic
antagonist propranolol is compared to norepinephrine. FIGURE 2.18 Optical isomers. Only in compound 6 do the func-
Because of the presence of the ether oxygen atom, the pri- tional groups A, B, and C align with the corresponding sites of
ority sequence of the functional groups about the chiral binding on the asymmetric surface.
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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 45

one enantiomer is capable of attaining the correct special Drug Membrane Selective
orientation to enable all three functional groups to inter- dose selectivity metabolism
act with their respective sites on the receptor surface. The
inability of the other enantiomer to achieve the same num-
ber of interactions with the hypothetical receptor surface
explains its reduced biologic activity. The Easson-Stedman
Nonspecific
Hypothesis states that the more potent enantiomer must Desired
response
Drug
receptor receptors.
be involved in a minimum of three intermolecular interac- Site of loss

tions with the surface of the biologic target and that the less
potent enantiomer only interacts with two sites. This can be FIGURE 2.20 Selective phases to which optical isomers can be
illustrated by looking at the differences in vasopressor activ- subjected before biologic response.
ity of R-(−)-epinephrine, S-(+)-epinephrine, and the achiral
N-methyldopamine (Fig. 2.19). With R-(−)-epinephrine,
the three points of interaction with the receptor site are point can provide enough of an influence to cause one
the substituted aromatic ring, b-hydroxyl group, and the enantiomer to produce a significantly better pharmaco-
protonated secondary ammonium group. All three func- logic effect than the other. Conversely, such processes
tional groups interact with their complementary sites on can also contribute to untoward effects of a particular
the receptor surface, resulting in receptor stimulation (in enantiomer. Differences in pharmacologic action among
this case). With S-(+)-epinephrine, only two interactions stereoisomers provides an excellent example of how not
are possible (the protonated secondary ammonium and all pharmacologic effects of a drug are necessarily ben-
the substituted aromatic ring). The b-hydroxyl group is eficial to the patient. Although there is no regulatory
located in the wrong place in space and, therefore, cannot prohibition on the development of racemic agents, it is
interact properly with the receptor. N-methyldopamine can reasonable that single enantiomer drugs will become the
achieve the same interactions with the receptor as S-(+)- overwhelming therapeutic choice in the future.
epinephrine; therefore, it is not surprising that its vasopres-
Diastereomers
sor response is the same as that of S-(+)-epinephrine and
less than that of R-(−)-epinephrine. As mentioned earlier, diastereoisomers are molecules
Not all stereoselectivity seen with enantiomers can be that are nonsuperimposable, non–mirror images. This
attributed to differences in the ability of the drug mol- type of isomer can result from the presence of more than
ecule to interact with its biologic target. Differences in one chiral center in the molecule, double bonds, or ring
biologic activity can also result from differences in the systems. These isomers have different physicochemical
ability of each enantiomer to reach the biologic target. properties, and as a result, it is possible that they can have
Because the biologic system encountered by the drug is differences in biologic activity.
asymmetric, each enantiomer can experience selective Molecules that contain more than one chiral center
penetration into membranes, metabolism, absorption probably are the most common type of drug-based dia-
at sites of loss (e.g., adipose tissue), and/or excretion. stereoisomers. Classic examples are the diastereoisomers
Figure 2.20 shows various phases that enantiomers can ephedrine and pseudoephedrine (Fig. 2.21). When a
encounter before reaching the biologic target. An enan- molecule contains two chiral centers, there can be as
tiomer cannot encounter stereoselective environments at
each of these points; however, enantioselectivity at any
H OH
HO H NHCH3
NHCH3 Enantiomers
H CH3
CH3 H
A
A A
(-)-Ephedrine (+)-Ephedrine
A
H O A H O A H O
O O O
H H H
Diastereomers Diastereomers
H H O H
H O H B H B H B
H H H H H
N CH3 N CH3 N CH3
H H H OH
H H H H HO H NHCH3
NHCH3
C CH3 H
C C CH3
H Enantiomers

R-(-)-Epinephrine S-(+)-Epinephrine N-Methyldopamine (-)-Pseudoephedrine (+)-Pseudoephedrine

FIGURE 2.19 Drug receptor interaction of R-(−)-epinephrine, FIGURE 2.21 Relationship between the diastereomers of ephed-
S-(+)-epinephrine, and N-methyldopamine. rine and pseudoephedrine.
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 46 PART I / PRINCIPLES OF DRUG DISCOVERY

H H
CH3 OH
N
(CH3)2N H 3C OH CH2OH

HO O NHCOCHCl2
O2N
H3C OH

Isomethadol Morphine Chloramphenicol

O OH C2H5O O
H CH3
N
H2N N
N
CH3 H
HO O COOH

Labetalol Enalapril

FIGURE 2.22 Examples of chiral drugs with two or more asymmetric centers.

many as four possible stereoisomers consisting of two assigned a priority of 1 or 2, depending on the atomic
sets of enantiomeric pairs. When considering an enan- number of the atom attached to the double bond. When
tiomeric pair of molecules, there is inversion of both chi- two substituents of higher priority are on the same side
ral centers. In diastereomers, there is inversion of only of the double bond, this isomer is given the designation
one chiral center. (Problem 9 at the end of this chapter of cis or Z. When the substituents are on opposite sides,
helps to illustrate this point.) Figure 2.22 shows several the designation is trans or E. The histamine H1-receptor
examples that contain two or more chiral centers and, antagonist triprolidine (Fig. 2.23) is a good example for
therefore, are diastereoisomeric (see Problem 10 at the demonstrating how this nomenclature system works.
end of this chapter). The E-isomer of triprolidine is more active both in vitro
Restricted bond rotation caused by carbon–carbon and in vivo, indicating that the distance between the
double bonds (alkenes or olefins) and similar systems, pyridine and pyrrolidine rings is critical for binding to
such as imines (C=N), can produce stereoisomers. These the receptor.
are also referred to as geometric isomers, although they Diastereoisomers (as well as enantiomers) can also
more properly are classified as diastereoisomers. In this be found in cyclic molecules. For example, the cyclic
situation, substituents can be oriented on the same side alkane 1,2-dimethylcyclohexane can exist as cis/trans-
or on opposite sides of the double bond. The alkene diastereoisomers, and the trans isomer can also exist as
2-butene is a simple example. an enantiomeric pair. In Figure 2.24, each of the trans-
enantiomorphs is depicted in the two possible chair con-
formations for the cyclohexane ring. Since cyclohexane
rings can exhibit significant conformational freedom,
this allows for the possibility of conformational isomers.
Isomers of this type will be discussed in the next sec-
tion. When two or more rings share a common bond
With 2-butene, it is readily apparent that the methyl (e.g., decalin), rotation around the bonds is even more
groups can be on the same or on opposite sides of the restricted. This prevents ring “flipping” from occurring,
double bond. When they are on the same side, the and as a result, diastereoisomers and enantiomers are
molecule is defined as the cis- or Z-isomer (from the generated.
German zusammen, meaning “together”); when they are
on opposite sides, the designation is trans- or E- (from
the German entgegen, meaning “opposite”). With simple
compounds, such as 2-butene, it is easy to determine 1 1
N 1 N
which groups in the molecule are cis or trans to one H
2
N
another. This becomes more difficult to determine,
however, with more complex structures, where it is less 2 2
H 2 N
obvious which substituents should be referred to when 1
naming the compound. In 1968, Blackwood et al. (22)
proposed a system for the assignment of “absolute” con- H3C H3C
figuration with respect to double bonds. Using the CIP
Z E
sequence rules, each of the two substituents attached
to the carbon atoms comprising the double bond are FIGURE 2.23
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Geometric isomers of triprolidine.

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 47

H3C CH3
CH3 the hydrogen atom being above this plane. What appears
CH3 to be a very minor change in orientation for the substit-
uent results in a very drastic change in the three-dimen-
cis sional shape of the molecule and in its biologic activity.
CH3 Figure 2.25 shows the diastereoisomers 5a-cholestane and
CH3 CH3
CH3
5b-cholestane as examples. The chemistry and pharmacol-
H3C ogy of steroids will be discussed in more detail in Chapters
CH3 28 (Adrenocorticoids), 40 (Men’s Health: Androgens),
trans
CH3
and 41 (Women’s Health: Estrogens and Progestins).
CH3
CH3

CH3
H3C Conformational Isomerism
CH3 Conformational isomerism takes place via rotation about
trans one or more single bonds. Such bond rotation results in
FIGURE 2.24 Diastereomers of 1,2-dimethylcyclohexane.
nonidentical spatial arrangement of atoms in a molecule.
This type of isomerism does not require much energy
because no bonds are broken. In the conversion of one
enantiomer into another (or diastereoisomer), bonds
are broken, which requires significantly more energy.
The neurotransmitter acetylcholine can be used to dem-
onstrate the concept of conformational isomers.

Each single bond within the acetylcholine molecule is

capable of undergoing rotation, and at room tempera-
ture, such rotations readily occur. Rotation around single
bonds Ca–Cb bond of acetylcholine was shown by Kemp
In the case of decalin, a two-ring system, the rings are and Pitzer (23) in 1936 not to be free but, rather, to have an
fused together via a common bond in either the trans or energy barrier, which is sufficiently low that at room tem-
cis configuration as shown. Steroids, a class of medicinally perature acetylcholine exists in many interconvertible con-
important compounds that consist of four fused rings formations (see Chapter 9). Rotation around the central
(three cyclohexanes and one cyclopentane), exhibit signifi- Ca–Cb bond produces the greatest spatial rearrangement
cantly different biologic activity when the first two cyclohex- of atoms compared to rotation around any other bond.
ane rings are fused into different configurations, referred Since the atoms at the end of some of the bonds within
to as the 5a- or 5b-isomers (Fig. 2.25). The a-designation acetylcholine are identical, rotation about several of these
indicates that the hydrogen atom in the 5-position is below bonds produces redundant structures when viewed along
the “plane” of the ring system; the b-designation refers to the Ca–Cb bond, and acetylcholine can be depicted in

H3C
CH3
CH3
H3 C

H
H
H H

5α-Cholestane

H3C CH3
CH3
H3C
H
H H

5β-Cholestane

FIGURE 2.25 The 5a and 5b conformations of the steroid nucleus cholestane.

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 48 PART I / PRINCIPLES OF DRUG DISCOVERY

OAc OAc OAc OAc of the functional groups of the lead compound are car-
H H
H
H
H
H N(CH3)3 (H3C)3N H ried out in order to improve its recognition, affinity, and
H
H H H H H H binding geometries of the pharmacophoric groups for the
N(CH3)3 N(CH3)3 H H targeted site (a receptor or enzyme); its pharmacokinet-
ics; or its reactivity and stability toward metabolic degrada-
anti or staggered gauche or skew conformers tion. The final step of the drug discovery process involves
conformer
rendering the lead compound into a drug candidate that
FIGURE 2.26 Anti and gauche conformations of acetylcholine. is safe and suitable for use in human clinical trials, includ-
ing the preparation of a suitable drug formulation.
the sawhorse or Newman projections, as shown in Figure Natural Product Screening
2.26. When the ester and trimethylammonium groups are Perhaps the most difficult aspect of drug discovery is
180° apart, the molecule is said to be in the anti, or stag- that of lead discovery. Until the late 19th century, the
gered, conformation (or conformer or rotamer). This development of new chemical entities for medicinal pur-
conformation allows maximum separation of the func- poses was achieved primarily through the use of natu-
tional groups and is the most stable conformation ener- ral products, generally derived from plant sources (see
getically. It is possible that other conformations are more Chapter 1). As the colonial powers of Europe discovered
stable if factors other than steric interactions are consid- new lands in the Western Hemisphere and colonized
ered (e.g., intramolecular hydrogen bonds). Rotation of Asia, the Europeans learned from the indigenous peo-
one end of the Ca–Cb bond by 120° or 240° results in the ples of the newly discovered lands of remedies for many
two gauche, or skew, conformations shown in Figure 2.26. ailments derived from herbs. Salicylic acid was isolated
These are less stable than the anti conformer, although from the bark of willow trees after learning that Native
some studies suggest that an electrostatic attraction Americans brewed the bark to treat inflammatory ail-
between the electron-poor trimethylammonium and elec- ments. Structural optimization of this lead compound
tron-rich ester oxygen atom stabilizes this conformation. (salicylic acid) by the Bayer Corporation of Germany
Rotation by 60°, 180°, and 240° produces the least stable resulted in acetylsalicylic acid, or aspirin, the first nonste-
conformations in which all of the atoms overlap, what are roidal anti-inflammatory agent. South American natives
referred to as eclipsed conformations. used a tea obtained by brewing Cinchona bark to treat
chills and fever. Further study in Europe led to the isola-
DRUG DESIGN: DISCOVERY AND STRUCTURAL tion of quinine and quinidine, which subsequently were
MODIFICATION OF LEAD COMPOUNDS used to treat malaria and cardiac arrhythmias, respec-
tively. Following “leads” from folklore medicine, chem-
Process of Drug Discovery ists of the late 19th and early 20th centuries began to seek
The process of drug discovery begins with the identifica- new medicinals from plant sources and to assay them for
tion of new, previously undiscovered, biologically active many types of pharmacologic actions. This approach to
compounds, often called “hits,” which are typically found drug discovery is often referred to as “natural product
by screening many compounds for the desired biologic screening.” Before the mid-1970s, this was one of the
properties. We will next explore the various approaches major approaches to obtaining new chemical entities
used to identify “hits” and to convert these “hits” into “lead” as “leads” for new drugs. Unfortunately, this approach
compounds and, subsequently, into drug candidates suit- fell out of favor and was replaced with the rational
able for clinical trials. Sources of “hits” can originate from approaches to drug design developed during that period
natural sources, such as plants, animals, or fungi; from (see next section). Heightened awareness of the fragil-
synthetic chemical libraries, such as those created through ity of ecosystems, especially the rainforests, has fueled
combinatorial chemistry or historic chemical compound a resurgence of screening products from plants before
collections; from chemical and biologic intuition from they become extinct. A new field of pharmacology, called
years of chemical–biologic training; from targeted/ratio- “ethnopharmacology,” which is the discipline of identi-
nal drug design; or from computational modeling of a tar- fying potential natural product sources with medicinal
get site such as an enzyme. Chemical or functional group properties based on native lore, has emerged as a result.
modifications of the “hits” are performed in order to Compounds isolated from natural sources are usually
improve the pharmacologic, toxicologic, physiochemical, tested in one or more bioassays for the ailment(s) that the
and pharmacokinetic properties of a “hit” compound into plant material has been purported to treat. Interestingly,
a “lead” compound. The lead compound to be optimized the treatment of different ailments can require different
should be of a known chemical structure and possess a methods of preparation (e.g., brewing, chewing, or direct
known mechanism of action, including knowledge of its application to wounds) or different parts of the same plant
functional groups (pharmacophoric groups) that are rec- (e.g., roots, stem, leaves, flowers, or sap). As it turns out,
ognized by the receptor/active site and are responsible each method of administration or part of the plant used
for that molecule’s affinity at the targeted receptor site. can produce one or more different chemical compounds
“Lead optimization” is the process whereby modifications
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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 49

Drug Discovery via Random Screening of Synthetic metabolites of known drug entities are isolated and
Organic Compounds assayed for biologic activity using either the same target
The random screening of synthetic organic compounds system or broader screen target systems. The broader
approach to the discovery of new chemical entities for screening systems are more useful if the metabolite
a particular biologic action began in the 1930s, after under evaluation is a chemical structure that was radi-
the discovery of the sulfonamide class of antibacteri- cally altered from the parent molecule through some
als. All compounds available to the investigator (natural unusual metabolic rearrangement reaction. In most
products, synthetic molecules), regardless of structure, cases, the metabolite is not radically different from the
were tested in the pharmacologic assays available at the parent molecule and, therefore, would be expected to
time. This random screening approach was also applied exhibit similar pharmacologic effects. One advantage of
in the 1960s and 1970s in an effort to find agents that evaluating this type of drug candidate is that a metabolite
were effective against cancer. Some groups did not can possess better pharmacokinetic properties, such as a
limit their assays to identify a particular type of biologic longer duration of action, better oral absorption, or less
activity but, rather, tested compounds in a wide variety toxicity with fewer side effects (e.g., terfenadine and its
of assays. This large-scale screening approach of drug antihistaminic hydroxylated metabolite, fexofenadine).
“leads” is referred to as high-throughput screening, As it turns out, the sulfonamide antibacterial agents were
which involves the simultaneous bioassay of thousands discovered in this way. The azo dye Prontosil was found to
of compounds in hundreds to thousands of bioassays. have only antibacterial action in vivo. It was soon discov-
These types of bioassays became possible with the advent ered that this compound required metabolic activation
of computer-controlled robotic systems for the assays via reduction of the diazo group to produce the active
and combinatorial chemistry techniques for the synthe- metabolite 4-aminobenzene sulfonamide (Fig. 2.27). The
sis of large numbers of compounds in small (milligram) sulfonamide mimics the physicochemical properties of
quantities. This type of random screening eventually PABA, a crucial component in microbial metabolism. It
gave way to targeted dedicated screening and rational is no surprise that the sulfonamide acts as a competitive
design techniques. inhibitor of the enzyme for which PABA is a substrate.
Drug Discovery from the Observation of Side Effects
Drug Discovery from Targeted Dedicated Screening An astute clinician or pharmacologist can detect a side
and Rational Drug Design effect in a patient or animal model that could lead, on
Rational drug design is a more focused approach that further development, to a new therapeutic use for a par-
uses greater knowledge (structural information) about ticular chemical entity. Discovery of new lead compounds
the drug receptor (targets) or one of its natural ligands as via exploitation of side-effect profiles of existing agents is
a basis to design, identify, or create drug “leads.” Testing discussed below.
is usually done with one or two models (e.g., specific One of the more interesting drug development sce-
receptor systems or enzymes) based on the therapeu- narios is that of the phenothiazine antipsychotics (see
tic target. The drug design component often involves Chapter 14). Molecules with this type of biologic activ-
molecular modeling and the use of quantitative struc- ity can be traced back to the first histamine H1-receptor
ture–activity relationships (QSARs) to better define the antagonists developed in the 1930s. In 1937, Bovet and
physicochemical properties and the pharmacophoric Staub (24) were the first to recognize that it should be pos-
groups that are essential for biologic activity. The develop- sible to antagonize the effects of histamine and, thereby,
ment of QSARs relies on the ability to examine multiple treat allergic reactions. They tested compounds that were
relationships between physical properties and biologic known to act on the autonomic nervous system and, eventu-
activities. In classic QSAR (e.g., Hansch-type analysis), an ally, discovered that benzodioxanes (Fig. 2.28) significantly
equation defines biologic activity as a linear free-energy antagonized the effects of histamine. During an attempt
relationship between physicochemical and/or structural
properties. It permits evaluation of the nature of inter-
NH2 O O
action forces between a drug and its biological target, as N N S NH2
azo
H2N S NH2
well as the ability to predict activity in molecules. These reductase
O O
approaches are better for the development of a lead com- H2N
pound into a drug candidate than for the discovery of a 4-aminobenzenesulfonamide
lead compound.
+

Drug Discovery via Drug Metabolism Studies NH2

NH2

New drug entities have been “discovered” as drug leads

H2N
through investigation of the metabolism of drug mol-
ecules that already are clinical candidates or, in some FIGURE 2.27 Metabolic conversion of prontosil to 4-aminoben-
instances, are already on the market. In this method, zenesulfonamide.
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 50 PART I / PRINCIPLES OF DRUG DISCOVERY

O O CHOCH2CH2N(CH3)2
CH2N(CH3)2 CH2N(CH3)2

Benzodioxanes Ethanolamines Diphenhydramine

S NCH2 CH N(CH3)2
CH3 NCH2CH2N(CH3)2
NCH2CH2N(CH3)2
N
CH3CH2

Phenothiazines Tripelennamine
(Promethazine) Ethylenediamines

Cl

S NCH2CH2CH2N(CH3)2

Chlorpromazine
(antipsychotic)

FIGURE 2.28 Development of phenothiazine-type antipsychotic drugs.

to improve the antihistaminergic action of the benzodi- Another example of how new chemical entities can
oxanes, it was discovered that phenyl substituted ethanol- be derived from biologically unrelated molecules is illus-
amines also demonstrated significant antihistaminergic trated by the development of the potassium channel
activity. Further development of this class generated two agonist diazoxide (Fig. 2.29). This molecule was devel-
different classes of antihistamines, the diphenhydramine oped as a result of the observation that the thiazide diuret-
class of antihistamines represented by diphenhydramine ics, such as chlorothiazide, not only exhibited diuretic
(Fig. 2.28) and the ethylenediamine class, represented by activity, due to inhibition of sodium absorption in the
tripelennamine (Fig. 2.28) (see also Chapter 32). distal convoluted tubule, but also demonstrated a direct
Incorporation of the aromatic rings of the ethylenedi- effect on the renal vasculature. Structural modification
amines into the rigid and planar tricyclic phenothiazine to enhance this direct effect led to the development of
structure produced molecules (e.g., promethazine) with diazoxide and related potassium channel agonists for the
good antihistaminergic action and relatively strong sedative treatment of hypertension (see Chapter 28).
properties (see also Chapter 32). At first, these compounds
were found to be useful as antihistamines, but their very Refinement of the Lead Structure
strong sedative properties led to their use as potentiating
agents for anesthesia (25). Further development to increase Determination of the Pharmacophore
the sedative properties of the phenothiazines resulted in Once a “hit” compound has been discovered for a particu-
the development of chlorpromazine in 1950 (26). lar therapeutic use, the next step is to identify the pharma-
Chlorpromazine was found to produce a tendency for cophoric groups. The pharmacophore of a drug molecule
sleep, but unlike the antihistamine phenothiazines, it also
produced a disinterest in patients with regard to their sur-
roundings (i.e., tranquilizing effects). In patients with psy- Cl N N CH
chiatric disorders, an ameliorative effect on the psychosis NH NH
H2NO2S S
and a relief of anxiety and agitation were noted. These O O
Cl
O
S
O
observations suggested that chlorpromazine had potential
Chlorothiazide Diazoxide
for the treatment of psychiatric disorders. Thus, what started (blockade of Na + resorption) (K+ channel agonist)
out as an attempt to improve antihistaminergic activity ulti-
mately resulted in an entirely new class of chemical entities FIGURE 2.29 Structural similarity of chlorothiazide (a diuretic) and
useful in the treatment of an unrelated disorder (27).
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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 51

is that portion of the molecule that contains the essential pharmacologic activity of the molecule. A change in the
functional group(s) that directly bind with the active site length of an alkyl chain by one CH2 unit or branch alters
of the biologic target to produce the desired biologic activ- the lipophilic character of the molecule and, therefore,
ity. Because drug–target interactions can be very specific its properties of absorption, distribution, and excretion.
(think of a lock [receptor] and key [drug] relationship), If the alkyl chain is directly involved in an interaction
the pharmacophore can constitute a small portion of the with the biologic target, then this type of alteration can
molecule. In many cases, a very structurally complex mol- influence the quality of those interactions. Molecules that
ecule can be “stripped down” to a simpler structure with are conformationally flexible can become less flexible if
retention of the pharmacophoric groups while maintaining branching is introduced at a key position of an alkyl chain
the desired biologic action. An example of this is the opioid or the alkyl chain is incorporated into a ring equivalent.
analgesic morphine, a tetracyclic compound with five chi- Changes in conformation can alter the spatial relation-
ral centers. Not only would structure simplification possibly ship between the pharmacophoric (functional) groups
provide molecules with fewer side effects, but a reduction in in the molecule and thereby influence interactions with
the number of chiral centers would greatly simplify the syn- the biologic target. Small structural changes are impor-
thesis of morphine derivatives. Figure 2.30 shows how the tant to consider in the design of structural analogues.
morphine structure has been simplified in the search for An example that demonstrates how an increase in
molecules with fewer deleterious side effects, such as respi- hydrocarbon chain length has significant effects not only
ratory depression and addiction potential. Within each class on potency, but also on drug action (agonist vs. antagonist)
are analogues that are less potent, equipotent, and many is provided by a series of N-alkyl morphine analogues (Fig.
times more potent than morphine. As shown in the figure, 2.31). In this series, homologation of R = CH3 (morphine)
the pharmacophore of morphine consists of a tertiary alkyl- to R = CH2CH2CH3 (N-propylnormorphine) produces a
amine that is at least four atoms away from an aromatic ring. pronounced decrease in agonist activity and an increase in
A more detailed discussion of the chemistry and pharma- antagonist activity. When further homologated by one met-
cology of morphine can be found in Chapter 20. hylene unit R = CH2CH2CH2CH3 (N-butylnormorphine),
the resulting analog is totally devoid of agonist or antago-
Alterations in Alkyl Chains: Chain Length, Branching, nist activity (i.e., the compound is inactive). Additional
and Rings increases in chain length (R = CH2CH2CH2CH2CH3 and
An increase or decrease in the length of an alkyl chain R = CH2CH2CH2CH2CH2CH3) produce compounds with
(homologation), branching, and alteration of ring increasing potency as agonists. When R is b-phenylethyl,
size can have a profound effect on the potency and the compound is a full agonist, with a potency approxi-
mately 14-fold that of morphine (28,29).
Branching of alkyl chains can also produce drastic
H H changes in potency and pharmacologic activity. If the mech-
H3C
N
OH H3C
N
anism of action is closely related to the lipophilicity of the
O
molecule, then hydrocarbon chain branching will result in
a less lipophilic compound and a significant alteration in
OH OH

4,5α-Epoxymorphinans Morphinans
H H
N
R OH

O
N
H3C R N
H3C OH

R Pharmacological activity
OH
CH3 Analgesic (morphine)
Benzomorphans
CH2CH3 Opioid agonist activity decreased
CH2CH2CH3 Opioid antagonist activity increased
CH3
N N CH2CH2CH2CH3 Inactive as opioid agonist or antagonist
H3 C H3C
H3C H
R CH2CH2CH2CH2CH3
O Opioid antagonist activity increased
CH2CH2CH2CH2CH2CH3
4-Phenylpiperidines Methadones
CH2CH2 14X potency of morphine
FIGURE 2.30 Morphine pharmacophore and its relationship to
analgesic derivatives. FIGURE 2.31
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Effect of alkyl chain length on activity of morphine.

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 52 PART I / PRINCIPLES OF DRUG DISCOVERY

biologic effect. This decrease in lipophilicity is a result of TABLE 2.7 Comparison of Physical Properties of N2O
the alkyl chain becoming more compact and causes less and CO2
disruption of the hydrogen-bonding network of water. If
the hydrocarbon chain is directly involved in interactions Property N2O CO2
with its biologic target, then branching can produce major
Viscosity at 20°C 148 × 10−6 148 × 10−6
changes in pharmacologic activity. For example, consider
the phenothiazines promethazine and promazine: Density of liquid at 10°C 0.856 0.858

Refractive index of liquid, D line 16°C 1.193 1.190

Dielectric constant of liquid at 0°C 1.593 1.582

Solubility in alcohol at 15°C 3.250 3.130

and molecules. The similarities among atoms described by

Langmuir resulted primarily from the fact that these atoms
The primary pharmacologic activity of prometha- contained the same number of valence electrons and came
zine is that of an antihistamine, whereas promazine is from the same columns within the periodic table. This con-
an antipsychotic. The only difference between the two cept of isosterism was limited to elements in adjacent rows
molecules is the alkylamine side chain. In the case of and columns, inorganic molecules, ions, and small organic
promethazine, there is an isopropylamine side chain, molecules, such as diazomethane and ketene. Table 2.7
whereas promazine contains an n-propylamine. In this shows a comparison of the physical properties of N2O and
case, simple modification of one carbon atom from a CO2 to illustrate Langmuir’s concept.
branched to a linear hydrocarbon radically alters the To account for similarities between functional groups
pharmacologic activity. with the same number of valence electrons but different
Positional isomers of aromatic ring substituents can also numbers of atoms, Grimm (32) developed his hydride
possess different pharmacologic properties. Substituents displacement law. This is not a “law” in the strict sense
on aromatic rings can alter the electron distribution but, rather, more an illustration of similar physical prop-
throughout the ring, which, in turn, can influence how erties among closely related functional groups. Table 2.8
the ring interacts with the biologic target. Aromatic ring presents an example of Grimm’s hydride displacement.
substituents can also influence the conformation of the Descending diagonally from left to right in the table,
flexible portion of a molecule, especially if the substitu- hydrogen atoms are progressively added to maintain
ents are located ortho to the same carbon attached to the the same number of valence electrons for each group
flexible side chain. Ring substituents influence the confor- of atoms within a column (thus the term “hydride”).
mations of adjacent substituents via steric interactions and Within each column, the groups are considered to be
can significantly alter interactions with the biologic target. “pseudoatoms” with respect to each another. Thus, NH2
is considered to be isosteric to OH, and so on. This early
view of isosterism did not consider the actual location,
Functional Group Modification: Bioisosterism motion, and resonance of electrons within the orbitals
Bioisosterism of these functional group replacements. Careful obser-
When a lead compound is first discovered, it often lacks vation of this table reveals that some groups do share
the required potency and pharmacokinetic properties similar physicochemical properties, but others have very
suitable for making it a viable clinical candidate. These different properties, despite having the same number
can include undesirable side effects, physicochemical of valence electrons. For example, OH and NH2 share
properties, other factors that affect oral bioavailability similar hydrogen-bonding properties and, therefore,
(see also Chapter 3), and adverse metabolic or excretion should be interchangeable if that is the only important
properties. These undesirable properties are often the criterion. The NH2 group is basic, whereas the OH is neu-
result of the presence of specific pharmacophoric (func- tral. Hence, at physiologic pH, the NH2 group exists in
tional) groups in the molecule. Successful modification
of the compound to reduce or eliminate these undesir-
able features without losing the desired biologic activity TABLE 2.8 Grimm’s Hydride Displacement “Law”
is the goal. Replacement or modification of specific phar-
macophoric (functional) groups with other groups hav- C N O F Ne
ing similar properties is known as “isosteric replacement”
CH NH OH FH
or “bioisosteric replacement.”
In 1919, Langmuir (30,31) first developed the concept CH2 NH2 OH2
of chemical isosterism to describe the similarities in physi-
CH3 NH3
cal properties among atoms, functional groups, radicals,
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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 53

its protonated or conjugate acid form and the molecule Burger (35) expanded this definition to take into account
becomes positively charged. If OH is being replaced by biochemical views of biological activity: “Bioisosteres are
NH2, the additional positive charge could have a signifi- compounds or groups that possess near equal molecular
cant effect on the overall physicochemical properties of shapes and volumes, approximately the same distribution
the molecule in which it is being introduced. The dif- of electrons, and which exhibit similar physical properties
ference in physicochemical properties of the CH3 group such as hydrophobicity. Bioisosteric compounds affect the
relative to the OH and NH2 groups is even greater. In same biochemically associated systems as agonist or antag-
addition to acid–base character, this “law” fails to take onists and thereby produce biological properties that are
into account other important physicochemical parame- related to each other.”
ters, such as electronegativity, polarizability, bond angles,
size, shape of molecular orbitals, electron density, and Classical and Nonclassical Bioisosteres
partition coefficients, all of which contribute significantly Bioisosteric groups can be subdivided into two catego-
to the overall physicochemical properties of a molecule. ries: classical and nonclassical bioisosteres. Functional
Instead of considering only partial structures, groups that satisfy the original conditions of Langmuir
Hinsberg (33) applied the concept of isosterism to entire and Grimm are referred to as classical bioisosteres.
molecules. He developed the concept of “ring equiva- Nonclassical bioisosteres do not obey steric and elec-
lents”—that is, functional groups that can be exchanged tronic definitions of classical bioisosteres and do not
for one another in aromatic ring systems without dras- necessarily have the same number of atoms as the func-
tic changes in physicochemical properties relative to the tional group that they replace. A wider set of compounds
parent structure. Benzene, thiophene, and pyridine illus- and functional groups are encompassed by nonclassical
trate this concept (Fig. 2.32). A –CH = CH- group in ben- bioisosteres that produce, at the molecular level, quali-
zene is replaced by the divalent sulfur, -S-, in thiophene, tatively similar agonist or antagonist action. In animals,
and a –CH = is replaced by the trivalent –N = to give pyri- many hormones and neurotransmitters with very similar
dine. The physical properties of benzene and thiophene structures and biologic actions can be classified as bioiso-
are very similar. For example, the boiling point of ben- steres. An example is the insulins isolated from various
zene is 81.1°C, and that of thiophene is 84.4°C (at 760 mammalian species. Even though these insulins can dif-
mm Hg). Pyridine, however, deviates, with a boiling point fer by several amino acid residues, they still produce the
of 115 to 116°C. Hinsberg therefore concluded that diva- same biologic effects. (If this did not occur, the use of
lent sulfur (-S- or thioether) must resemble –C = C- in insulin to treat diabetes would have had to wait another
shape, and these groups were considered to be isosteric. 60 years for recombinant DNA technology to allow pro-
Note that hydrogen atoms are ignored in this compari- duction of human insulin.)
son. Today, this isosteric relationship is seen in many
drugs e.g., H1-receptor antagonists (Fig. 2.32).
It is difficult to relate biologic properties to physi-
TABLE 2.9 Classical Bioisosteres (Groups Within the
cochemical properties of individual atoms, functional Row Can Replace Each Other)
groups, or entire molecules, because many physicochemi-
cal parameters are involved simultaneously and, therefore, Monovalent bioisosteres
are difficult to quantitate. Simple relationships as described F, H
earlier often do not hold up across the many types of bio- OH, NH
F, OH, NH or CH3 for H
logic systems seen with medicinal agents. That is, what can SH, OH
work as an isosteric replacement in one biologic system Cl, Br, CF3
can not work in another. Because of this, it was necessary
to introduce the term “bioisosterism” to describe func- Divalent bioisosteres:
tional groups related in structure that have similar biologic —C=S, —C=O, —C=NH, —C=C—
effects. Friedman (34) introduced the term bioisosterism
and defined it as follows: “Bioisosteres are (functional) Trivalent atoms or groups:
groups or molecules that have chemical and physical simi- C N
,
larities producing broadly similar biological properties.” H
P , As

N Tetrasubstituted atoms:
N(CH3)2 N(CH3)2
N N

N C P As
S

Ring equivalents:
Tripelennamine Methaphenilene

FIGURE 2.32 Isosteric substitution of thiophene for benzene and S N O

benzene for pyridine.
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 54 PART I / PRINCIPLES OF DRUG DISCOVERY

What can be a successful bioisosteric replacement C. Trivalent atoms and groups

for a given molecule that interacts with a particular bio- D. Tetrasubstituted atoms
logic target quite has often no effect or abolishes bio- E. Ring equivalents
logic activity in another. Thus, the use of bioisosteric II. Nonclassical bioisosteres
replacement (classical or nonclassical) in the design of A. Exchangeable groups
new chemical entities (drug discovery) is highly depen- B. Rings versus noncyclic structure
dent on the biologic system under investigation. No
hard-and-fast rules exist to determine which bioisosteric CLASSICAL BIOISOSTERES Substitution of hydrogen with
replacement is going to work with a given molecule, fluorine is a common monovalent isosteric replace-
although as the following tables and examples demon- ment. Sterically, hydrogen and fluorine are quite simi-
strate, some generalizations are possible. Each category lar, with their van der Waals’ radii measuring 1.2 and
of bioisostere can be further subdivided as shown below, 1.35 Å, respectively. Because fluorine is the most elec-
and examples are provided in Tables 2.9 and 2.10: tronegative element in the periodic table, any differ-
ences in biologic activity resulting from replacement
I. Classical bioisosteres
of hydrogen with fluorine can be attributed to this
A. Monovalent atoms and groups
property.
B. Divalent atoms and groups
A classic example of hydrogen replacement by fluo-
rine is development of the antineoplastic agent 5-fluoro-
TABLE 2.10 Nonclassical Bioisosteric Replacements uracil from uracil. Another example is shown in Figure
2.33, in which the chlorine of chlorothiazide has been
Compounds Bioisosteric Replacement References replaced with bromine or a trifluoromethyl group.
O NH O N 40
For each of the substitutions, the electronic (s, where
Cl N Cl N s+ is electron withdrawing and s− is electron donat-
N
H
NH2 N NH2
ing) and hydrophobic (p) properties of each group
H2N N NH2 H2N N NH2 are maintained relatively constant, but the size of each
group varies significantly, as indicated by the Taft steric
COOH N 41
N
N parameter (Es).
N Figure 2.34 shows an example of classical isosteric sub-
H
stitution of an amino group for a hydroxyl group in folic
acid. The amino group is capable of mimicking the tauto-
meric forms of folic acid and providing the appropriate
COOH COOH 42
hydrogen bonds to the enzyme active site.
NH
N O
A tetravalent bioisosteric replacement study was done
Cl Cl H by Grisar et al. (36) with a series of a-tocopherol ana-
logues (Fig. 2.35). a-Tocopherol has been shown to
scavenge lipoperoxyl and superoxide radicals and to
O R 43 accumulate in heart tissue. This is thought to be part of
N
its mechanism of action to reduce cardiac damage result-
OCH3
O
N
ing from myocardial infarction. All of the bioisosteric
N analogues were found to produce similar biologic activity.
CH3 N
CH3
NONCLASSICAL BIOISOSTERES As mentioned earlier, nonclas-
OH OH 44 sical bioisosteres are replacements of functional groups

R N
S

H H NH
H2NO2S S
O O
NH2 NH2 45
N N N N
R= Cl Br CF3
N N N N
HO
O
HO σ +0.23 +0.23 +0.54

π +0.71 +0.86 +0.88

OH OH
Es -0.97 -1.16 -2.40
S COOH COOH 46
NH2 NH2 FIGURE 2.33 Isosteric replacement of chlorine in thiazide diuret-

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 55

H2N N N OH
O
H COOH
N N C NH
N
COOH Folic acid X = OH
X
Aminopterin X = NH2 HO
OH
1,2-bis-(2-ethyl-4-hydroxyphenyl)
ethane
H2N N N H2N N N H
H2N N N
HO
N HN N
N R N R N R OH
OH O
Diethylstilbestrol (trans)
O

H2N N N H2N N N H
H2 N N N HO
N HN N
N R N R N R HO
Estradiol
NH2 NH NH
OH
FIGURE 2.34 Isosteric replacement of OH by NH2 in folic acid
and possible tautomers of folic acid and aminopterin. Diethylstilbestrol (cis)
OH

not defined by classical definitions. Some of these groups,

however, mimic spatial arrangements, electronic prop- HO
erties, or some other physicochemical property of the 1,6-bis-(p-hydroxyphenyl)hexane
molecule or functional group critical for biologic activ-
ity. One example is the use of a double bond to position FIGURE 2.36 Noncyclic analogs of estradiol.
essential functional groups into a particular spatial con-
figuration critical for activity. This is shown in Figure 2.36
with the naturally occurring hormone estradiol and the examples of successful bioisosteric replacements are
synthetic analogue diethylstilbestrol. The trans isomer of shown in Table 2.10, and a more detailed description of
diethylstilbestrol has approximately the same potency as the role of bioisosterism can be found in the review by
estradiol, whereas the cis isomer is only one fourteenth as Patani and LaVoie (42).
active. In the trans configuration, the phenolic hydroxy
groups mimic the correct orientation of the phenol and PEPTIDE AND PROTEIN DRUGS
alcohol in estradiol (37,38). This is not possible with the
cis isomer, and more flexible analogues (Fig. 2.36) have Not all drugs are small molecules as described thus far.
little or no activity (39,40). Some very important therapeutic agents are peptidic in
Another example of a nonclassical replacement is nature (e.g., insulin, calcitonin) and, due to their physi-
that of a sulfonamide group for a phenol in catechol- cal chemical properties, generally cannot be delivered
amines (Fig. 2.37). With this example, steric factors orally and must be administered parenterally. Peptides
appear to have less influence on receptor binding than and proteins are very similar in that they are made up
acidity and hydrogen-bonding potential of the func- of units, or residues, of amino acids that are linked by
tional group on the aromatic ring. Both the phenolic amide bonds, also referred to as peptide bonds. There
hydroxyl of isoproterenol and the acidic proton of the is no definitive number of amino acid residues that
arylsulfonamide have nearly the same pKa (∼10) (41). delineates a peptide from a protein. However, the term
Both groups are weakly acidic and capable of losing a peptide refers generally to molecules that contain 15 to
proton and interacting with the biologic target as anions
(Fig. 2.37). Because the replacement is not susceptible Isoproterenol Soterenol
to metabolism by catechol O-methyltransferase, it has OH
OH
also the added advantage of increasing the duration of H
N
H
N
action and making the compound orally active. Other
HO HO
O N
O
H O S H
X = N(CH3)3 CH3
HO
X
Nonclassical bioisoteres
X = P(CH3)3 O O
O
X = S(CH3)2

α-Tocopherol X = C 14H29 FIGURE 2.37 Bioisosteric replacement of m-OH of isoproterenol

with a sulfonamido group and similar hydrogen-bonding capacity
FIGURE 2.35 Tetravalent bioisosteres of a-tocopherol. to a possible drug receptor.
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 56 PART I / PRINCIPLES OF DRUG DISCOVERY

50 amino acids. Molecules composed of more than 50 functional group “backbone” that includes a basic amine
residues are generally referred to as proteins. attached to the a-carbon of an acidic carboxylic acid.
There are 20 naturally occurring amino acids that The a-carbon for each amino acid is substituted with a
serve as the building blocks for both peptide and protein unique side chain. The amino acid side chains contrib-
drugs (Table 2.11). Each amino acid contains a common ute significantly to the physical chemical properties of

TABLE 2.11 The Twenty Natural Occurring Amino Acids

Name R General
Structure
H
CO2 H
H2 N

3 Letter code Single Structure R = pKa of side

Letter code chain

Glycine Gly G -H none

Alanine Ala A -CH3 none

Valine Val V –CH(CH3)2 none

Isoleucine Ile I –CH(CH3)CH2CH3 none

Leucine Leu L –CH2CH(CH3)2 none

Proline Pro P none

N CO 2 H
H
(side chain highligted)

Phenylalanine Phe F –CH2-C6H5 none

Tryptophan Trp W CH 2 none

N
H

Methionine Met M –CH2CH2SCH3 none

Cysteine Cys C –CH2SH (acidic) ∼8

Serine Ser S –CH2OH none

Threonine Thr T –CH(CH3)OH none

Tyrosine Tyr Y (acidic) ∼10

CH2 OH

Arginine Arg R H (basic) ∼12.5

CH2 CH2 CH2 N NH2
NH

Lysine Lys K –CH2CH2CH2NH2 (basic) ∼10.5

Histidine His H CH2 (basic) ∼6

NH
N

Asparagine Asn N –CH2CONH2 none

Glutamine Gln Q –CH2CH2CONH2 none

Aspartic Acid Asp D –CH2COOH (acidic) ∼3.8

Glutamic Acid Glu E –CH2CH2COOH (acidic) ∼4

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 57

O O R
H
N N Trans peptide bond
N R H O
H
O

R R
FIGURE 2.38 A tripeptide, Ala-Val-Gly, indicating the planarity of the Cis peptide bond
N O
peptide bonds caused by the restricted rotation around the amide bond. O H

FIGURE 2.39 Cis/trans peptide bond configuration.

the peptide that is formed from a unique sequence of

amino acids.
As previously mentioned, the amino acid residues (i.e., functional groups) present in a given structure.
are linked by amide bonds, as shown in Figure 2.38. As might be expected, the types and number of func-
Each carboxylic acid forms an amide bond with the tional groups present in the side chains dictate how
amine group of the next amino acid in the sequence. much more or less polar the peptide is compared to a
As with other amide bonds, conjugation between the small-molecule drug. It is certainly plausible that pep-
lone pair of electrons on the nitrogen atom and the tide-based drugs will not have optimal logP values for
adjacent carbonyl group results in the amide bond hav- passive absorption across membranes and, given their
ing partial double-bond character due to a resonance large MW, will not readily cross membranes (see also
structure as shown in Figure 2.38. This property has two Chapter 3).
major consequences: 1) the amide bond is therefore
co-planar; and 2) there is restricted rotation around the Metabolism/Degradation of Peptide and Protein
C–N bond (Fig. 2.38). Because of this restricted rota- Drugs
tion, there are two conformations possible, cis and trans Peptides and proteins are metabolized extensively by
(Fig 2.39). The trans-conformation is lower in energy enzymes in the gastrointestinal tract, blood, interstitial
due to fewer steric interactions (similar to that found fluid, vascular bed, and cell membranes, which results in
with a carbon–carbon double bond) and is favored. very poor oral absorption and a short half-life for these
When proline is one of the amino acid residues, the molecules. The primary route of metabolism of peptides
cis-conformation can be favored as a result of the amine and proteins involves hydrolysis of the peptide bonds
group being part of a pyrrolidine ring. For this reason, that link the amino acids by enzymes called peptidases.
the presence of proline in peptides and proteins is asso- Some of these peptidases exhibit specificity for certain
ciated with a “kink” or bend in the overall conforma- amino acid sequences or have specificity for either the
tion of the peptide chain. amino or carboxyl terminus of the peptide (exopepti-
dase). For example, carboxypeptidases cleave off one
Physical Chemical Properties of Peptides C-terminal residue, dipeptidyl carboxypeptidases cleave
Since the a-amine and a-carboxylic acid of each amino dipeptides from the C terminus, aminopeptidases cleave
acid are involved in the peptide backbone (except at off one N-terminal residue, and amidases (endopep-
each terminus of the chain), the basic and acidic nature tidases) cleave internal peptide bonds. There are also
of these functional groups does not contribute to the peptidase subclasses that exhibit specificity for certain
overall physical chemical properties of the molecule. amino acid sequences within the peptide or at either
The functional groups found within the amino acid of the termini. Some peptidases (e.g., dipeptidyl pep-
side chains are what are integral to the physicochemi- tidase IV) have been found to catalyze the degradation
cal properties of the peptide or protein and represent of naturally occurring peptides (e.g., GLP-1) (Fig. 2.40)
important points of interaction with the correspond- (see also Chapter 37).
ing biologic target. Examination of Table 2.11 shows
that the functional groups found within the amino
acid side chains can be basic (e.g., amine, guanidine,
Subject to proteolytic degradation
imidazole), acidic (e.g., carboxylic acid, phenol, thiol), catalyzed by dipeptidyl peptidase
neutral (e.g., thioether, amide), or hydrocarbon (e.g.,
alkyl, aromatic rings) in nature. All of the functional
groups found in amino acid side chains were discussed His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu
previously as components of small-molecule drugs.
Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg
The primary differences in physical chemical prop-
erties between peptides and small molecules are due
GLP-1
to their large size (molecular weight [MW]) and, as
a result, the sheer number of different side chains FIGURE 2.40 GLP-1 degradation by dipeptidyl peptidase IV.

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 58 PART I / PRINCIPLES OF DRUG DISCOVERY

SUMMARY Codeine phosphate Cyproheptadine

hydrochloride
Medicinal chemistry involves the discovery of new chemi-
cal entities and the systematic study of the SARs of these Haloperidol Phenytoin
compounds for disease state management. Such studies 7. Calculate the logP value for each of the following:
provide the basis for development of better and therapeuti- Aspirin Carphenazine
cally safer medicinal agents from lead compounds found Codeine Cyproheptadine
from natural sources, random screening, systematic screen-
ing, and focused rational design. Drug design goals include Haloperidol Chlordiazepoxide
increasing the potency and duration of action of newly dis- Phenytoin
covered compounds and decreasing adverse side effects. 8. Using the Merck Index or other source, find the
For the pharmacist, it is also important to understand chemical structures for the following empirical
how the physicochemical properties influence the phar- formulae. List as many physicochemical proper-
macokinetic properties of the medicinal agents being ties as possible for each compound, and compare
dispensed. Such knowledge will help the pharmacist not them within each group of isomers:
only to better understand the clinical properties of these C4H10O2 C5H8O
compounds but also to anticipate the properties of newly
C5H11O2 C7H7NO2 C8H8O2
marketed agents. An understanding of the chemical prop-
erties of the molecule will allow the pharmacist to antici- C12H17NO3
pate formulation problems (especially IV admixtures), as C20H30O2
well as potential adverse interactions with other drugs as 9. Using the Cahn-Ingold-Prelog rules, assign the
the result of serum protein binding and metabolism. absolute configuration to each chiral center of
ephedrine and pseudoephedrine (Fig. 2.21).
PROBLEMS 10. For the compounds shown in Figure 2.22, indi-
cate, using an*, where the chiral centers are in
The following problems are provided for additional each molecule.
study: 11. Draw each possible stereoisomer for chloram-
1. Calculate the percent ionization of amobarbital at phenicol and enalapril. Assign the absolute ste-
pH 2.0, 5.5, and 8.0. What trend is seen? reochemistry to each chiral center.
2. Calculate the percent ionization of phenylpropa- 12. I. Draw the Newman projection along the
nolamine at pH 2.0, 5.5, and 8.0. Compare these CH3–N bond of acetylcholine in the stag-
results with those obtained in Problem 1. gered conformation. Rotate the bond 120°
3. Calculate the percent ionization of sulfacetamide and 240°. Are these rotameters conforma-
in the stomach, duodenum, and ileum. Draw the tional isomers? Explain why or why not.
structure of the predominate form of the drug in II. Repeat the above exercise with the N1–C2
each tissue. bond of acetylcholine.
4. Referring to Figure 2.15, redraw each compound 13. Draw the three most stable rotameters of norepi-
in its ionized form. nephrine. Of these rotameters, is there the possi-
5. For the organic functional groups listed in Table 2.4, bility of an intramolecular interaction that would
name each functional group, and redraw them, stabilize what normally would be considered an
showing all potential hydrogen bonds with water. unstable rotameter? Explain.
6. Using the empiric method of Lemke, predict the
water solubility for each of the following mol-
ecules (Note: Water solubility is defined as >1%
solubility):
Aspirin Carphenazine maleate
Chlordiazepoxide Codeine

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 CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 59

TABLE 2.12 Drug Structures not Included in Text for Problems at End of Chapter 2
Problem # Drug Name Drug structure

3 Sulfacetamide O
H CH3
H2N S N
O O

6+7 Aspirin CO2H

O CH3

6+7 Chlordiazepoxide NHCH3

N

Cl N
O

6+7 Carphenazine maleate

S
CO2H
N
CO2H
(CH2)3
N
2
N
OH

6+7 Codeine H3C

N

H3CO
O
OH

6+7 Cyproheptadine

N CH3

6+7 Phenytoin
O

NH
N
H
O

6+7 Haloperidol OH
F N
O
Cl

11 Chloramphenicol OH
H
OH
H
N
O2N
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H
O
CHCl2

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 60 PART I / PRINCIPLES OF DRUG DISCOVERY

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