WO2001022952A2

WO2001022952A2 - Use of tace inhibitors

Info

Publication number: WO2001022952A2
Application number: PCT/EP2000/009218
Authority: WO
Inventors: Andrew Faller; Ruth Judik Mayer
Original assignee: Smithkline Beecham P.L.C.; Smithkline Beecham Corporation
Priority date: 1999-09-25
Filing date: 2000-09-21
Publication date: 2001-04-05
Also published as: AU7420800A; GB9922825D0; WO2001022952A3

Abstract

Inhibitors of tumor necrosis factor alpha converting enzyme (TACE) are useful in the treatment or prophylaxis of allergy, allergic asthma, atopic dermatitis and other atopic diseases.

Description

Medical Use

This invention relates to a medical use and in particular to the use of inhibitors of tumor necrosis factor (TNF)α converting enzyme (TACE) for the treatment of allergy.

Matrix metalloproteases such as collagenase, stromelysin and gelatinase are known to be involved in connective tissue breakdown. Known classes of matrix metalloprotease inhibitors include derivatives of hydroxamic acid, phosphonates and thiols.

International Patent Application, Publication Number WO 93/20047 discloses that inhibitors of the matrix metalloproteases, especially derivatives of hydroxamic acid, are potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis or invasion.

WO 93/20047 discloses various derivatives of hydroxamic acid including those from the following patent publications: USP 4599361, EP-A-0236872, EP-A-0274453, WO 90/05716, WO 90/05719, WO 91/02716, EP-A-0489577, EP-A-0489579, EP-A-0497192 and WO 92/13831.

TNFα is a pro-inflammatory cytokine which is released from stimulated cells by specific cleavage of a 76-amino acid signal sequence in the inactive precursor to generate the mature form. The cleavage of TNFα has been reported to be carried out by a metalloprotease (Gearing, A.J.H. et al, (1994) Nature 370, 555-557; McGeehan, G.M. et al, (1994) Nature 370, 558-561; Mohler, K.M. et al, (1994) Nature 370, 218-220). Compounds reported to inhibit the cleavage of TNFα by TACE can be broadly described as matrix metalloprotease inhibitors, particularly of the hydroxamic acid class.

TNFα is induced in a variety of cell types in response to bacteria, endotoxin, various viruses and parasites, so that one physiological function ascribed to TNFα is a contribution to the inflammatory response to acute infection by bacteria, parasites, etc (Dinarello, C.A. (1992) Immunol. 4, 133-145). Overproduction of TNFα has been implicated in disease states such as rheumatoid arthritis, septic shock, Crohn's disease and cachexia (Dinarello, 1992). Inhibition of processing of TNFα to the mature, active form would therefore be beneficial in the treatment of these inflammatory disorders. TNFα may also contribute to the destruction of tissue in autoimmune disease although it is not an initiating factor in these diseases. Confirming the importance of TNFα in rheumatoid arthritis, TNFα antibodies have been shown to reduce the severity of disease in short term studies in rheumatoid arthritis models (Elliott, M.J., et al (1993) Arthrit. Rheum. 12, 1681-1690; Elliott et al (1994) Lancet 344, 1125-1127).

It has been found that compounds which inhibit the action of matrix metalloproteases (e.g. collagenase, stromelysin and gelatinase) are effective inhibitors of TACE and the release of human TNF. It has now surprisingly been found that such compounds inhibit the production of IgE. Inhibitors of the matrix metalloproteases are therefore potentially usef l for the treatment or prophylaxis of allergy, allergic asthma, atopic dermatitis and other atopic diseases. Known classes of matrix metalloprotease inhibitors include derivatives of hydroxamic acid, phosphonic acid and thiols, all of which have been shown to inhibit TNF release.

Accordingly, the present invention provides the use of an inhibitor of TACE for the manufacture of a medicament for the treatment or prophyaxis of allergy, allergic asthma, atopic dermatitis and other atopic diseases.

In a further aspect the invention provides a method for the treatment or prophylaxis of allergy, allergic asthma, atopic dermatitis and other atopic diseases, which method comprises the administration of a TACE inhibitor to a human or non-human mammal in need thereof.

The invention also provides a pharmaceutical composition for the treatment or prophylaxis of allergy, allergic asthma, atopic dermatitis and other atopic diseases, which comprises a TACE inhibitor and optionally a pharmaceutically acceptable carrier therefor.

Suitable inhibitors are set out in the table and include the hydroxamic acid derivatives disclosed in WO 90/05716, WO 90/05719, WO 91/02716, WO 92/13831, WO 93/20047, EP- A-0236872, EP-A-0274453, EP-A-0489577, EP-A-0489579, EP-A-0497192 and USP 4599361.

Suitable matrix metalloprotease inhibitors also include the thiols and phosphonic acids disclosed in EP 0273689 and EP 0320118. The contents of WO 90/05716, WO 90/05719, WO 91/02716, WO 92/13831, WO 93/20047, EP-A-0236872, EP-A-0274453, EP-A-0489577, EP-A-0489579, EP-A- 0497192, USP 4599361, EP 0273689 and EP 0320118 and the other patent publications referred to in the table, are incorporated herein by reference, including the specific examples disclosed in these patent publications.

It is to be understood that the pharmaceutically acceptable salts, solvates and other pharmaceutically acceptable derivatives of the above mentioned matrix metalloprotease inhibitors are also included in the present invention.

The inhibitors mentioned herein may exist in several different isomeric forms including stereoisomeric forms. Unless specifically sated to the contrary herein with respect to particular compounds, all isomers including stereoisomers and mixtures of isomers, such as racemic mixtures, are included within the present invention.

The inhibitors of the invention may be prepared by use of any appropriate conventional method, for example the inhibitors disclosed in patent publications WO 90/05716, WO 90/05719, WO 91/02716, WO 92/13831, WO 93/20047, EP-A-0236872, EP-A-0274453, EP-A- 0489577, EP-A-0489579, EP-A-0497192, USP 4599361, EP 0273689 and EP 0320118 may be prepared by the methods disclosed therein.

The isomers, including stereoisomers, of the inhibitors of the present invention may be prepared as mixtures of such isomers or as individual isomers. The individual isomers may be prepared by any appropriate method, for example individual stereoisomers may be prepared by stereospecific chemical synthesis starting from chiral substrates or by separating mixtures of enantiomers using known methods.

It is preferred that the inhibitors are isolated in substantially pure form.

As used herein the term "matrix metalloprotease inhibitor" and equivalent terms means any compound which inhibits any member of the family of zinc and calcium dependent endopeptidases (matrix metalloproteases) that have the ability to degrade components of the connective tissue matrices. Matrix metalloproteases and their inhibition are discussed by inter alia Hooper, FEBS Letters 1994, 354,1-6; Gordon et al., Clinical and Experimental Rheumatology 1993, 1 l(Suppl. 8), S91-S94;

Woessner, FASEB 1991, 5, 2145-2154; and Birkedal-Hansen, Critical Reviews in Oral Biology and Medicine 1993, 4(2), 197-250. Assays for inhibition of collagenase, stromelysin, and gelatinase are described in WO 90/05719, page 67, WO 90/05719, page 68, and EP-A-0489 577, pages 25-26, respectively. The present invention comprehends the use of compounds which are deemed active in any one of these assays, as well as the specific compounds set out in the Table.

As stated herein an inhibitor of TACE has useful medical properties relating to atopic disease. Preferably the active compounds are administered as pharmaceutically acceptable compositions.

The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example in the form of a spray, aerosol or other conventional method for inhalation, for treating respiratory tract disorders; or parenteral administration for patients suffering from heart failure. Other alternative modes of administration include sublingual or transdermal administration.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Compositions of this invention may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns for example diameters in the range of 1-50 microns, 1-10 microns or 1-5 microns. Where appropriate, small amounts of other anti-asthmatics and bronchodilators, for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.

The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration. A preferred range for inhaled administration is 10-99%, especially 60-99%, for example 90, 95 or 99%.

Microfine powder formulations may suitably be administered in an aerosol as a metered dose or by means of a suitable breath-activated device.

Suitable metered dose aerosol formulations comprise conventional propellants, cosolvents, such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, desiccants such as calcium sulphate and density modifiers such as sodium chloride.

Suitable solutions for a nebulizer are isotonic sterilised solutions, optionally buffered, at for example between pH 4-7, containing up to 20mg/ml of compound but more generally 0.1 to lOmg/ml, for use with standard nebulisation equipment.

An effective amount will depend on the relative efficacy of the compounds of the present invention, the severity of the disorder being treated and the weight of the sufferer. Suitably, a unit dose form of a composition of the invention may contain from 0.1 to lOOOmg of a compound of the invention (0.001 to lOmg via inhalation) and more usually from 1 to 500mg, for example 1 to 25 or 5 to 500mg. Such compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from lmg to lg for a 70 kg human adult and more particularly from 5 to 500mg. That is in the range of about 1.4 x 10^~2 mg/kg/day to 14 mg/kg/day and more particularly in the range of about 7 x 10^~2 mg/kg/day to 7 mg/kg/day. TABLE

TABLE contd.

TABLE contd.

BIOLOGICAL TEST METHODS

Procedure 1: The ability of test compounds to inhibit TACE was investigated by use of the following procedure.

The extracellular domain of TACE was expressed following the methods described (Moss, M.L., et al (1997) Nature 385, 733-736) and enzymatic activity measured using a fluorescent quench peptide based on the TNF cleavage site (Bachem). Compounds were diluted from DMSO stock solutions into 100 ul 10 mM HEPES, pH 7.5 containing 10-50 uM substrate and enzyme to give at least a 10-fold increase in fluorescence within 30 min. Percent inhibition was determined relative to controls without inhibitor.

Procedure 2: The ability of test compounds to inhibit the formation of human IgE in vitro was investigated using the following procedure. Peripheral blood leukocytes (mononuclear cells) from consenting, atopic donors were purified from whole blood by Ficoll-Pacque gradient. Cells were resuspended and cultures were maintained in HB101 medium (Irvine Scientific, Irvine, CA) with 10 % fetal bovine serum (FBS) at 37°C in 5 % CO2 atmosphere. Cells were incubated in 24- well plates seeded at 1X10^ cells/ml for up to 14 days in the presence of 1-50 ng/ml recombinant human IL-4 (rhIL-4, prepared at SmithKline Beecham), 50 ng/ml anti-CD40 Ab (Pharmingen), and compounds added to various concentrations from stock solutions of DMSO to a final DMSO concentration of no more than 0.1 %. At the end of the incubation period, cells were removed by centrifugation and IgE, IgG and sCD23 in the cell-free supernatant were determined by ELISA.

Claims

1. Use of an inhibitor of tumor necrosis factor alpha converting enzyme (TACE) for the manufacture of a medicament for use in the treatment or prophylaxis of allergy, allergic asthma, atopic dermatitis and other atopic diseases.

2. Use according to claim 1 wherein the inhibitor of TACE is an inhibitor of a matrix metalloprotease.

3. A method for the treatment or prophylaxis of allergy, allergic asthma, atopic dermatitis and other atopic diseases, which method comprises the administration of an effective amount of an inhibitor of TACE to a human or non- human mammal in need thereof.

4. A pharmaceutical composition for the treatment or prophylaxis of allergy, allergic asthma, atopic dermatitis and other atopic diseases, which comprises an inhibitor of TACE.

5. A pharmaceutical composition as claimed in claim 4, further comprising a pharmaceutically acceptable carrier.

6. A pharmaceutical composition as claimed in claim 5, for use in the treatment or prophylaxis of allergy, allergic asthma, atopic dermatitis and other atopic diseases.

7. A pharmaceutical composition as claimed in claim 4, wherein the inhibitor of TACE is a matrix metalloprotease inhibitor.

8. Use according to Claims 1 and 2, a method according to Claim 3 or a pharmaceutical composition according to any one of claims 4 to 7, substantially as hereinbefore described with reference to the Table.