JPH06508614A - Use of β-cell tropin (ACTH22-39) antagonists in the treatment of type 2 diabetes and related diseases - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] ■β-cell tropin (ACTH22-3) in the treatment of type diabetes and related diseases 9) Use of antagonists The present invention provides medicaments containing compounds and compositions and conditions associated with the disease Regarding the use of such drugs in the treatment of Type II diabetes) .

■Type diabetes, or non-insulin-dependent diabetes, occurs in humans as well as dogs and cats. is a serious and common metabolic disease state in other mammals such as Currently suffering from the disease There are no commercially available drugs that provide effective treatment for this condition.

Amylin was recently isolated from amyloid mass extracted from type II diabetic pancreas. Polypeptides [Pronodals of the National Academy of Sciences] Proc, Natl, Acad, Sc i, USA), Volume 84, Pages 8628-8632, December 1987. Ami Phosphorus is used in the body to control the distribution of carbohydrate energy (as glucose). was described as playing an active part in the endocrine homeostasis mechanism of especially, Amylin (1) suppresses the release of insulin from β-cells in the islets of Langerhans. (2) By making muscle cells ignore insulin, bone Disclosure of inhibition of basic insulin-stimulated glycogen synthesis in muscle muscles [WO39106135]. ■ Type diabetes and especially insulin resistance. It has been described that this is an effect of excessive secretion of amylin.

β-cell-tropin (β-CT) is a monocytogene of genetically obese (oblob) mice. Neurointermediate 1obes perifusates (superfusates) [Veroraf- Beloff-Chafn et al., F.E.B. Niss Letters ( FEBS Lett, ), (1980) 117.303-307].

β-CT has a range of biological activities. (1) It is the substimulatory concentration (su glucose in the bstimulatory concentrations) Insulin release from isolated perfused rat pancreas [Dunmore and Bet. Loraf-Chain (Dunmore & Be1off-Chain), Jar Nar of Endocrinology (J.

Endocrinol, ) (1982) 92.15-211, and Peri Release of insulin from perifused islets of Langerhans [Billingham et al., Research of Endocrinology] Nology (J, E ndocrinol, ) (1982) 94.125- 1301 to elicit a monophasic response. (2) It is a high concentration of glucose allows biphasic release of insulin from the perfused pancreas induced by [Beloff-Chain et al., Biochemical Science Transactions (Biochem, Soc, Tr ans, ) (1981) 9.522-5241゜(3) It is It has an insulin-like effect in promoting lipogenesis [Watkinson and Beth Roluff Chain (Watkinson & Be1off-Chain), Lumon and Metapolis Research (Horm, Metab, Res,) (1984) 16.55-58 (Suppl, )].

β-CT is characterized as adrenocorticotropin (ACTH)-(22-39). [Be1off-Chain et al., Nature] - (London) (Nature (London)), 301, (1983) 25 5-2581, its hormonal properties have been demonstrated in obese mouse plasma [Billingham lingham et al., 1982] and human plasma [Salvatoni (5alvat. oni) et al., Journal of Endocrinology (J, Endocrinology) ol, ) (1986) 110.303-3071 as evidenced by its presence in be done. Synthesis of β-CT was performed using the mild solid phase method (mild 5 solid phase method). rocedures) [Biochemical & Official Research - Biochem, and Biophys, Res, Come, ) (1983), Volume 114, No. No. 2, pp. 763-766].

Certain modifications to the structure of β-CT modulate its ability to release insulin. It is known that [Niss Dunmore et al. Iochemical Journal (Bjochem, J.) (1987) 244.79 7-8001° It has now been found that the adipogenic activity of β-CT can be modulated. .

β-CT was also found to play a critical role in regulating amylin release. Ta. In particular, β-CT may cause increased amylin release, thereby , has been shown to contribute to the development of insulin resistance.

Therefore, β-CT is responsible for the development of type II diabetic state due to increased insulin release, In particular, in the development of hyperinsulinemia, resulting insulin resistance, and , in the development of insulin resistance due to increased amylin release, and increased It has been shown to play a central role in the development of adipogenic obesity.

Modulating the formation or release of β-CT, or modulating the biological activity of β-CT, ■Type diabetes, hyperinsulinemia, and symptoms related to hyperinsulinemia (hyperinsulinemia) lipidemia, hypertension and atherosclerosis), insulin resistance, and obesity. and may offer therapeutic potential for symptoms associated with type diabetes, such as hyperglycemia and hyperglycemia. .

Therefore, the present invention provides a method for the formation, release or biological treatment of β-cell tropin (β-CT). the administration of a non-toxic, effective amount of a compound that modulates biological activity. In mammals, hyperinsulinemia, symptoms associated with hyperinsulinemia, hyperemia How to treat symptoms associated with type diabetes, such as glycemia, insulin resistance, and obesity I will provide a.

In one aspect, the invention provides methods for treating hyperinsulinemia and hyperinsulinemia-related It provides a method for treating the symptoms of In a further aspect, the invention provides a method for treating obesity. The present invention provides a treatment method for

Symptoms associated with hyperinsulinemia include hyperlipidemia, hypertension, and atheroma. One example is sexual arteriosclerosis.

One compound is one that modulates the formation of β-cell tropin. one compound regulates the release of β-cell tropin. One compound is β-cell It modulates the biological activity of tropin.

Certain compounds that modulate the biological activity of β-CT include β-CT antagonists. - A compound that inhibits the biological activity of CT.

An example of a β-CT antagonist is an antibody specific for β-CT, preferably a β-CT antagonist. - Non-competitive antagonists such as monoclonal antibodies specific for CT.

Further examples of β-CT antagonists include competitive β-CT antagonists.

Competitive β-CT antagonists are β-CT or β-CT agonists for β-CT receptors. It is an antagonist that competes with

Examples of competitive β-CT antagonists include ineffective β-CT agonists. impossible A β-CT agonist still has the ability to bind to β-CT receptors. induces a decreased biological response, preferably a pharmaceutically relevant biological response. It is a β-CT agonist that has been structurally modified to have no induction.

Examples of ineffective agonists include cross-linking agonists.

Suitable crosslinking agonists include crosslinked β-CT or crosslinked fragments of β-CT. Ru.

Examples of non-active agonists include substituted β-CT or substituted fragments of β-CT. Ru. The terms "substituted β-CTJ" and "substituted fragment of β-CT" refer to the amino acid sequence β-CT or amino acids with altered or structurally modified amino acids derived from the normal sequence. or a fragment thereof.

Further examples of competitive β-CT antagonists are antibodies directed against the β-CT receptor, preferably It is a monoclonal antibody.

In a further aspect, the present invention provides β-cell toxins for use as effective therapeutic agents. Provides compounds that modulate the formation, release or biological activity of β-CT It is something that

In particular, the present invention is useful for treating type III diabetes, hyperinsulinemia, and hyperinsulinemia. Treatment of type diabetes with associated symptoms, such as hyperglycemia, insulin resistance and obesity modulating the formation, release or biological activity of β-cell tropin (β-CT) The present invention provides a compound that has the following properties.

In a further aspect, the present invention provides treatment for type 1 diabetes mellitus, or hyperinsulinemia, high insulin Symptoms related to phosphatemia, such as hyperglycemia, insulin resistance and obesity Beta-cell tropin (beta-CT) for the manufacture of drugs for the treatment of conditions related to urinary disease provides for the use of compounds that modulate the formation, release or biological activity of .

Ineffective β-CT agonists are manufactured by appropriate conventional methods; thus, e.g. For example, cross-linked β-CT or cross-linked fragments of β-CT can be chemistry) 17.1978.1499, International Japan National of Peptide and Protein Research (Iinterna) tional J.

Peptide & Protein Res, ), 27.1986.285- 92 and Pierce (P1erce), 1989 Handbook and Gene Ral Catalog (Cross-Linking Regents) (Handbook) and General Catalog (Cross-1inking A conventional paper such as that disclosed in Manufactured by peptide crosslinking technology.

In addition, the substituted β-CT or the substituted fragment of β-CT is Ido Synthesis Practical Approach (Solid Phras) ePeptjde　5ynthesis　-a　Practical　Appr. och), E. Atherton (E.

Atherton), R.C. Shepherd Publishers (R,C,5 heppardPub, ), IRL Pres. s) by conventional peptide chemistry techniques such as those disclosed in .s).

β-CT antagonists are determined by the specific way in which β-CT interacts with β-CT receptors. It appears to be particularly convenient to produce when First, β-CT receptor including the identification of the active site of β-CT that interacts with the body. Once such information is established, Association of β-CT or its fragments that may be disabled by substitution or cross-linking Amino acid residue identity can be more easily determined.

Crystallographic analysis of the structure of β-CT co-crystallized with the receptor or part of the receptor analyzes the interaction between β-CT and its receptor. For such analysis Therefore, these factors are the most important in the interaction between β-CT and its receptor. A amino acid residue is measured and then substituted, e.g., to generate an antagonist. Or it turns out that it is cross-linked.

Additionally, structural analysis of β-CT versus β-CT receptor interactions revealed that peptides and the appropriate molecular shape of the non-peptide organic inhibitor and any other necessary structure for the inhibitor. Architectural features are determined.

Antibodies against β-CT receptors can be prepared using appropriate conventional methods [Proceedings of the National Academy of Sciences (Proe) .

Natl, Acad, Sci, USA) (1982), 79.7312-731 61 to produce antibodies such as monoclonal antibodies under the control of β-CT receptors. It can be obtained by making the Thus, purification or portions of the β-CT receptor by immunization with purified preparations or cells with high concentrations of β-CT receptors. β-CT receptors in suitable test animals such as BALB/C, BALB/C or other similar mouse strains. Antibodies against the condition can be raised. Remove the pancreas from the animal and remove it. Lymphocytes can be fused to mouse myeloma cell lines. High technology based on known technology After screening of hybrids, stable hybrids that form antibodies against β-CT receptors are identified. Isolate the ibrid. Such activity may be due to the antibody's radiolabeled β-CT (e.g. 125 ■ Prevents the binding of labeled β-6-tele or 3H-β-CT) to its receptor It can be shown by ability. Then, the screening techniques described below By using monoclonal antibodies, monoclonal antibodies can be tested for their antagonistic activity. Wear.

Further studies include the use of anti-idiotype antibodies. anti-idiotype antibodies , raised against monoclonal antibodies directed against β-CT, resulting in anti-id type, of course, without the activation activation associated with β-CT binding, the β-CT receptor have complementary binding affinities for the site. Block viral binding to cells The use of anti-idiotype antibodies is known [Journal of Immunology]. J. Immunol (1983), 131.2539-2541. Or Med.

■Tsu (1987) 317.219-2241゜Regulating the biological activity of β-CT Compounds that It is identified by In the calyx, effective β-CT antagonists are those that block β-CT receptors. By measuring whether the biological activity of β-CT is reduced under receptor pressure. It is identified by one suitable β-CT receptor receptor adipose tissue or adipocyte; or a suitable cell line such as 3T3-LL or 3T3-F442 cells. Seem. Other suitable β-CT receptor receptor drained pancreas, isolated pancreatic islets, pancreas β-cells, or appropriate cell lines such as HIT or RIN cells.

An example of an in vitro screen is in the presence of a β-CT source and In the presence or absence of phosphorus, glucose uptake by cells and/or phosphorus To determine the effect of an effective β-CT antagonist on the synthesis of dilglycerol Contains: Decreased uptake compared to control indicates antagonistic activity. in vitro screening A further example of lean is β-cell tropin-induced insulin and and/or inhibition of amylin release.

Alternatively, adipose tissue or pancreatic islet cells, or a suitable Plasma membranes derived from cell lines can be placed in receptor binding assays, thereby , the ability of antagonists to prevent binding of β-CT to its receptors immunoassay, ELISA or time-resolved fluorescence techniques (ti+me-resolved It can be monitored by fluorescent technology).

To determine the properties of a compound that modulates the formation or release of β-CT, first It is necessary to determine the nature of the metabolic control of β-CT formation from the pituitary gland. this For example, isolated pituitary neuromedial lobe, or whole pituitary and pituitary cell lines. By incubating with various concentrations of candidate molecules, intermediate metabolites and both biologically active peptides and signal molecules such as non-peptide hormones. whether the molecule has a positive effect or effect on β-CT formation and/or release. is measured by measuring which of the negative effects it has. various sigs The response of the pituitary tissue to nulls may be due to the formation of β-CT and/or its release into the medium. can be determined by measuring the release of Then use a similar method to The child's ability to block this mechanism can be tested.

β-CT can be synthesized by the method described above, such as ACTH and corticotrophin-like Specific cleavage of precursor molecules such as intermediate peptides (CLIP, ACTH18-39) It may also be formed by cutting. The method for controlling β-CT formation is the action of the enzymes involved. and/or suppressing the synthesis of the enzyme.

Test method for determining that a specific compound modulates the biological activity of β-CT The method is similar to conventional test methods; for example, the method used is It is similar to the conventional method used to measure production activity.

For example, white or brown adipocytes in the presence of β-CT and labeled glucose, It can be incubated in the presence or absence of the test compound. Next, practice The scintillation counting method is used to detect lipids in the presence or absence of test compounds. The amount of labeled glucose incorporated into fat cells as lipid is measured.

The particular compounds used are manufactured by appropriate methods. For example, if the compound If the antibody is raised against β-CT, it is produced by conventional antibody formation methods. Ru. One particular method involves injecting the test animal with β-CT the required number of times and administering it for an appropriate period of time. harvesting the antibodies formed in the test animal after, for example, 18 weeks. .

An example of another test method is to test isolated pancreatic islets [bilingata] in the presence or absence of a test substance. BilLingham et al., or Journal of Endocrinology. -(J.

Endocrinol) (1982) 94.125-130] or HIT Alternatively, a pancreatic β-cell line such as RIN cells can be incubated with β-CT and then to determine the effect of the test substance on insulin and/or amylin release. Including.

Release of insulin and amylin from the islets or cell lines can be achieved using conventional radioisotopes. It can be measured by immunoassay method.

Identification of β-CT receptor sites on pancreatic islets and adipose tissue indicates direct antagonism of its activity. This makes it possible to supply

The formation, release or biological activity modulating compounds of the invention may be administered as such. or preferably as a pharmaceutical composition comprising a pharmaceutically acceptable carrier. It may also be administered by

Therefore, the present invention provides a method for the formation, release or biological treatment of β-cell tropin (β-CT). A pharmaceutical composition comprising a compound that modulates biological activity and a pharmaceutically acceptable carrier. It also has something to offer.

Compounds that modulate the formation, release or biological activity of β-cell tropins are also included in the invention. It seems to be part of it.

Hereinafter, compounds that modulate the formation, release, or biological function of β-cell tropins are referred to as “ Compound of the present invention".

As used herein, the term "pharmaceutically acceptable" refers to human and veterinary medicine. Compounds, compositions and components for use in clinical use.

Suitable non-human mammals include dogs and cats.

The composition may optionally be in the form of a tablet with instructions for use. L Arashi.

Generally, the pharmaceutical compositions of the present invention are suitable for oral administration, but also for injection and transdermal absorption. Compositions for administration by any other route are also contemplated.

Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. . Other fixed unit dosage forms such as powders in single/double doses can also be used.

According to conventional pharmaceutical practice, carriers include diluents, fillers, disintegrants, wetting agents, lubricants, etc. Consisting of brighteners, colorants, flavoring agents or other customary auxiliaries.

Typical carriers include, for example, microcrystalline cellulose, starch, starch glycerin, Sodium cholate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, sulphate Magnesium thearate, sodium lauryl sulfate, or sodium chloride (It is mentioned.

Most preferably, the composition is formulated in unit dosage form. force) force/ru unit throw The value is usually between 0.1 and 100019, more typically between 0.1 and 500. It contains active ingredients in the range of 0.1 to 25,019 degrees.

Conveniently, the compounds of the invention are administered as a pharmaceutical composition as defined above; The form forms a particular aspect of the invention.

■ In the treatment of symptoms associated with type diabetes, the compounds of the present invention can be used in adults aged 70 & 9. The total daily dose ranges from 0.1 to 6000u, more commonly about 1 to 1500119 It is administered in such a manner as to be administered from 1 to 6 times a day at doses as described above.

The following examples illustrate the invention but are not intended to limit it in any way. a: Fatty rats (fa/fa) and fat-free controls, 12-20 weeks old. (Fa/'> or Fa/Fa) was used.

pancreatic perfusion Dunmore and Be O-77-Chei: / (Dunmore and Be 1off-Chain), Journal of Endocrinology (J, End ocrinol) (1982) 92.15.21. Pancreases from male adipose rats and nonadipose littermates were isolated and then So, I perfused it. The perfusion buffer was Dunmore and Berolough-Chain (Dunmore more and Be1off-Chain) (1982) (loc, l Dextran T40 (Fax) was added as described in Variants containing 3% Pharmacia and 1% high purity BSA. Krebs-Ringer-bicarbonate buffer.

The isolated preparation was then stabilized for 15 minutes in (“low glucose”) perfusion buffer. (after) perfusion with: 1. Low glucose (5,6 o1/l) buffer for 5 minutes; 2. 0.5-1. O 1. High glucose (1.5 min) for 5 min. 6, 7 mmol/I) buffer for 10 minutes.

Fractions were collected for 1 minute each at a flow rate of 5.0 mA'/min. Approach on the ice Nin (Traysylol, Baver) Fractions were collected in tubes containing 1800 K IU. assay Fractions were stored at -20° until.

Measurement of blood glucose, plasma insulin, and β-cell tropin Heparin ( Vlasov (Pularin, approximately 200 units/IIA') and Abrotin ( Contains Trasylol, 400 K I U/mA') Collect blood into a tube to a depth of approximately 5 cm (1), and remove protein from the sample just before measuring glucose concentration. The remaining material was centrifuged. Supernatant plasma was frozen at -20' until assayed.

Assay.

Glucose assay: uranyl acetate (URACX Boehrin Glucose oxidase/peroxide Measured spectrophotometrically using the sidase method.

Insulin assay: Dunmore and Berolough chain (Dunmore andBelow-Chain) (1982) (loc, cit, ) Plasma and and the insulin present in the perfusion samples. That is, the sample has a high titer molar A suitable dilution of Mott's insulin antiserum (1:30000 giving 50% binding) ) and +15 iodinated bovine insulin (iodine assayed in triplicate. Rat insulin (Nova,) Standards (diluted in plasma assay buffer (sodium phosphate) or perfusion buffer) used as. Cellulose coated with secondary antibody (donkey anti-guinea pig Ig) by addition of Sac-Cel (Sac-Cel, Washington) and subsequent centrifugation. , antibody-bound insulin was separated from free insulin. LKB Rack Gamma Solid Sha Measure the number of bonds with a cooling counter, and calculate the nuclear force')n9-1: Connection f:P C-AT: rz hit-9- (Opus PCV) TeRI ACALC program Insulin calculations were performed by LKB.

Amylin assay: Peninsula Laboratories Limited (Penins Lyophilized reagents supplied by ula Laboratories Ltd, ) Amylin was radioimmunoassayed using. Donkey anti-rabbit Ig (Sac - Binding and free binding performed using Sac-Cell, Washington) The supplier's assay method was followed except for the isolation of myrin. All standard dilutions ( Perfusion buffer decaprotinin (400KIU/■l) and perfusion samples in triplicate and assayed. Counts and calculations were performed as for insulin RIA. Ta.

Statistical analysis: method for unpaired or paired observations as desired The test was used.

Hanging Insulin and amylin secretion from isolated perfused fat-rich rat pancreas: β-C T and the resulting effects of high glucose concentrations Perfused with β-CT (0.5-1.0 nsol/i') for 5 minutes before changing. As a result, as previously reported [Dunmore and Berolough Chain (Du nmore and Be1off-Chain) (1982), loc, cit, ] A monophasic release of insulin occurred. fa/fa basal release from the pancreas Total insulin secretion (Δinsulin) in excess of It was 4.8 times larger (Table 1). Amylin secretion (Δamylin) is a secretion of insulin. It was very similar to the case, and there was a similar difference (4.5 times) between the two groups. . The molar ratio of insulin: amylin during β-CT stimulation of isolated pancreas was 42:1 to 48:1 without fat and 31:1 to 49:1 with fa/fa , slightly increased.

The effect of high glucose perfusion after pre-β-CT stimulation is due to the above-mentioned glucose alone. The test was different. High glucose yields 2.1 times more fat than from no fat Excess fat induces insulin release from the pancreas and was not previously stimulated with β-CT. It induced a 1.7 times greater insulin release than from the supernumerary pancreas. Amylin secretion is , a very large increase: fat secretion was 3.9 times greater than without fat, β-C It was 2.0 times larger than the fatty ones that were not preperfused with T.

According to the method of Rodbell (1964) with some modifications. Brown adipocytes were isolated. Two males weighing 1509 under halothane anesthesia. Brown adipose tissue between the shoulder blades was removed from rats. Glucose 5.6mmo l/j! and Talebsulin with bovine serum albumin 4.0% (W/V). Place the tissue in a Petri dish containing gar bicarbonate (KRB, p)I'7.4). Ta. Any adherent white fat was removed and the tissue was treated with KRB (5.6 mmol/7 grams). lucose and 4% albumin). in a shaking water bath at 37°C. 2 hours, glucose 5.6 wmol//.

Albumin 4% and collagenase (Serva Chemicals) micals)) 1, the tissue was digested in KRB with Omq/me. this Gas (02/CO295+5) was passed through the buffer throughout the period.

The digested tissue was then filtered through a 200μ mesh and fresh KRB (5,6 o1/l glucose and 4% albumin) and resuspended the cells at 80% Centrifuged for 1 minute at 0×g. Remove the buffer wash and add the cells to 5 ml of fresh buffer. Suspended. Measure this initial cell suspension using a hemocytometer to measure cell number. A liquid sample was used.

incubation Tritiated glycogen in the presence or absence of β-cell tropin antiserum (80:1 dilution) In the presence of lucose (D-[3-3H]glucose, 0.5 μCi/vial), Different insulins (14,4nff1ol/l) or β-cell tropins (10 KRB (5,6 mmol/r glucose and 4% (w/v) albumin) for 1 h in a shaking water bath at 37°C. 50μ aliquots of the suspension were incubated. Glucose uptake into lipids is a non-aqueous Anti-inflammatory fluid (Betafluor), National Overnight in Kusei Agnostics (National D 1 anostics) to extract and then measure beta luminescence on a scintillation counter. Therefore, it was measured. During this period, gas was passed through the fat cells without interruption.

By Beloff-Chain et al. (1980) From the incubation of mouse neural medial lobe by the disclosed method, this The β-cell tropin used in the study was isolated.

Generation of β-cell tropin antiserum β-cell tropin (40Qnol) and tyrotropin were added to 1ml of 0.1M phosphate buffer. Globulin (100 nmol) was dissolved. Glutaraldehyde (0.02M solution) 1.5 liters of liquid was added dropwise over 15 minutes, and the mixture was incubated overnight at 4°C. did. The conjugate was then dialyzed overnight against distilled water to remove glutamate. The dehyde was removed and the conjugate was treated with the next immunization and two boosters, respectively. - Freeze in total 50%, 25% and 25% aliquots sufficient to perform the injection. Dry. This amount of conjugate is sufficient to immunize one rabbit. It was.

- For the next immunization, take up the lyophilized conjugate in tap water 11/ Emulsify with 1.5 ml of complete adjuvant and add 0.1 liter of aliquot The back of a Dutch halfflop rabbit Intramuscular injections were given at multiple sites in the mid and flank.

For boosting immunization, take the lyophilized conjugate in 1 ml of tap water. Emulsify with 1.5 ml of Freund's complete adjuvant and add 0. ll11 aliquots , - Intramuscular injections were given at multiple sites 12 and 18 weeks after the next inoculation. secondary boo Blood samples were collected daily for determination of antibody titers, starting on day 3 after star immunization. did.

Blood was allowed to clot for 4 hours at room temperature and then overnight at 4°C. conventional radio immuno Antibody titers were measured in the assay system.

Hanging β-cell tropin is an important factor in the uptake of glucose into lipids, i.e., lipogenesis. produced irritation similar to surin. Differences between insulin-treated cells and controls and The differences between β-CT treated cells and controls were both statistically significant (P <0.05). There are no significant differences in the effects between insulin and β-cell tropin. There wasn't. The β-CT antibody completely blocks the β-CT response and increases the basal rate of adipogenesis. significantly decreased. ′ Ro0rororororoOrororo Rororororoclaw 1-J -J-cvc hehe atom 00000Dt/Ll/IQ田U,,,,,,,N@PCT/G Continuation of B 9210107B front page (71) Applicant: Chain, Benjamin Michael London, N.K. W 11.8 AG, 829 Finchley Road (72) Inventor Cawthorn, Michael Anthony UK Lee Katie 18.5ets Kuskiyou, Nibutsum, Ní Towley Bottom Road, Great Page ( No address displayed SmithKline Beecham Pharmaceuticals (72) Inventor: Berotshu Chain, Ann UK MK 18.1 E.g. -The University of Patskingham (No street address displayed)

Claims (22)

[Claims] 1. Compounds that modulate the formation, release or biological activity of β-cell thrombin. 2. Modulate the formation, release or biological activity of β-cell tropin (β-CT) A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier. 3. Modulate the formation, release or biological activity of β-cell tropin (β-CT) type II diabetes in a mammal, comprising administering a non-toxic effective amount of the compound; Methods of treating symptoms associated with type II diabetes. 4. Requests for treatment of hyperinsulinemia and symptoms associated with hyperinsulinemia The method described in claim 3. 5. Symptoms related to hyperinsulinemia include hyperlipidemia, hypertension and atherosclerosis. 5. The method according to claim 4, wherein the disease is atherosclerosis. 6. 4. The method of claim 3 for the treatment of obesity. 7. Claim 3 wherein the compound that modulates the biological activity of β-CT is a β-CT antagonist. 6. The method according to any one of 6 to 6. 8. 8. The method of claim 7, wherein the β-CT antagonist is a non-competitive antagonist. 9. Claim 7 or 8, wherein the β-CT antagonist is an antibody specific to β-CT. How to put it on. 10. 8. The method of claim 7, wherein the β-CT antagonist is a competitive β-CT antagonist. 11. A claim that the competitive β-CT antagonist is cross-linked β-CT or a cross-linked fragment of β-CT The method according to item 10. 12. Forms of β-cell tropin (β-CT) for use as effective therapeutic substances Compounds that modulate production, release, or biological activity. 13. For use in the treatment of type II diabetes or symptoms associated with type II diabetes 13. The compound according to claim 12, wherein 14. For the treatment of hyperinsulinemia and symptoms associated with hyperinsulinemia A compound according to claim 12 or 13. 15. Symptoms associated with hyperinsulinemia are hyperlipidemia, hypertension and atherosclerosis. 15. The compound according to claim 14, which is an arteriosclerotic compound. 16. 13. A compound according to claim 12 for the treatment of obesity. 17. A claim in which the compound that modulates the biological activity of β-CT is a β-CT antagonist. The compound according to any one of 12 to 16. 18. 18. A compound according to claim 17, wherein the β-CT antagonist is a non-competitive antagonist. 19. Claim 17, wherein the β-CT antagonist is an antibody specific for β-CT; or The compound described in 18. 20. 18. A compound according to claim 17, wherein the β-CT antagonist is a competitive β-CT antagonist. 21. A claim that the competitive β-CT antagonist is cross-linked β-CT or a cross-linked fragment of β-CT The compound according to item 20. 22. For the manufacture of drugs for the treatment of type II diabetes or conditions related to type II diabetes modulate the formation, release or biological activity of β-cell tropin (β-CT) Use of compounds.