Method and structure for inhibiting activity of serine elastases

• US 6,777,403 B2
• Filed: 12/23/2002
• Issued: 08/17/2004
• Est. Priority Date: 06/17/1999
• Status: Expired due to Fees

• Current Assignee: Accuthera Inc.
• Original Assignee: Cortech, Inc. (Kent International Holdings, Inc.)
• Inventors: Cheronis, John C.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Patel, Sudhaker B.
• Application Number:
  US10/329,057
• Publication Number:
  US 20030134856A1
• Time in Patent Office: 603 Days
• Field of Search: 514/183, 514/19, 514/256, 514/269, 514/274, 514/398, 514/397, 514/364, 544/98, 544/242, 544/309, 544/335, 544/336, 548/122
• US Class Current: 514/183
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 233/72 Two oxygen atoms, e.g. hydantoin
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06052 Val-amino acid
• CPC Class Codes: C07K 5/06139 with the first amino acid being heterocyclic

Abstract

Therefore, it is critical that the roles these enzymes play in biological processes outside of extracellular matrix degradation or remodeling be understood in order to assess their potential as targets for therapeutic intervention, and to design safe, conveniently produced, orally active inhibitors. Elastase inhibitors can differ with respect to their ability to inhibit different elastases. As a result, the spectrum of elastases inhibited by a specific drug candidate as well as the spectrum of activities these enzymes have with respect to proteins other than elastin are properties to consider in evaluating the drug candidates.

Claims

1. A serine elastase inhibitor, comprising:

an agent in a pharmaceutically acceptable carrier having a chemical structure including a seine elastase recognition moiety and a warhead moiety wherein the serine elastase recognition moiety includes any of compounds 2 through 27 in FIG. 5;

R₂ and R₃ are selected from the group consisting of H, phenly, cyclohexyl, and morpholino such that R₂ may not be the same as R₃ within a structure and R₄ is H or

the agent providing balanced inhibitory activity with respect to a plurality of serine elastases.

2. An inhibitor according to claim 1, wherein the plurality of elastases include neutrophil elastase and PR-3.

3. An inhibitor according to claim 2, wherein inhibition of neutrophil elastase by the agent has a first inhibitory constant and inhibition of PR-3 by the agent has a second inhibitory constant such that the first and second constants differ by no more than two orders of magnitude.

4. An inhibitor according to claim 3, wherein the first and second constants differ by a factor no larger than fifty-fold.

5. An inhibitor according to claim 4, wherein the first and second constants differ by no more than one order of magnitude.

6. An inhibitor according to claim 1, wherein one of the serine elastase recognition moiety and the warhead moiety contains a carbonyl group, the serine elastase recognition moiety contains a first submoiety including an R₁ sidechain, the warhead moiety contains a heterocycle warhead submoiety, a carbonyl carbon of the carbonyl group directly attached to a carbon of the heterocycle warhead submoiety and to the first submoiety.

7. An inhibitor according to claim 1, wherein the serine elastase recognition moiety includes a plurality of first submoieties.

8. An inhibitor according to claim 6, wherein the first submoiety is directly attached to a carbon of the warhead moiety.

9. An inhibitor according to claim 8, wherein the serine elastase recognition moiety further includes the following structure:

wherein R₂ and R₃ are selected from the group consisting of H, phenyl, cyclohexyl, and morpholino, such that R₂ may not be the same as R₃ within a structure.

10. An inhibitor according to claim 9, wherein the first submoiety includes an R₁ side chain which is selected from the group consisting of (—

CH₃), (—

CH₂CH₃), (—

CH₂CH₂CH₃), (—

CH₂CH₂CH₂CH₃), (—

CH₂CH₂—

S—

CH₃), (—

CH₂—

S—

CH₃), (—

CH₂CH₂—

O—

CH₃), (—

CH₂—

O—

CH₃), and (—

CH₂—

O—

CH₂CH₃).

11. An inhibitor according to claim 8, wherein the warhead moiety is alternatively selected from the group consisting of:

non-oxadiazole heterocycles including benzoxazole and substituted benzoxazole;

perfluorinated alkylketones including trifluoromethyl ketone and pentafluoroethyl ketone;

halomethyl ketone; and

boronic acid.

12. A method of inhibiting the activity of a plurality of seine elastases, comprising:

administering to an environment in which serine elastases are present, an effective amount of a compound according to claim 1.

13. A method according to claim 12, wherein a plurality of serine elastases include neutrophil elastase and PR-3.

20. An inhibitor according to claim 1, wherein the plurality of elastases includes at least one of endovascular elastase or endothelial elastase.

21. A method according to claim 11, wherein the plurality of elastases includes at least one of endovascular elastase or endothelial elastase.

14. A compound of the formula:

wherein Z is selected from the group consisting of any of the compounds 2-27 described in FIG. 5;

R₁ is selected from the group consisting of (—

CH₃), (—

CH₂CH₃), (—

CH₂CH₂CH₃), (—

CH₂CH₂CH₂CH₃), (—

CH₂CH₂—

S—

CH₃), (—

CH₂—

S—

CH₃), (—

CH₂CH₂—

O—

CH₃), (—

CH₂—

O—

CH₃), and (—

CH₂—

O—

CH₂CH₃);

R₂ is selected from the group of phenyl, cyclohexyl, morpholino, H;

R₄ is H or,

R₅ is selected from alkyl, alkenyl, haloalkyl, haloalkenyl, alkynyl being linear or branched;

a phenyl, phenylalkenyl, or phenylalkyl optionally substituted with halogen, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, arylcarboxamido, alkylthio, or haloalkylthio groups being linear or branched;

a heteroaryl, heteroarylalkyl or heteroarylalkenyl wherein the heteroaryl group is a monocyclic five or six membered ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with halogen, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, alkenyl, alkynyl, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, arylcarboxamido, alkylthio or haloalkylthio groups being linear or branched; and

X and Y are independently O, S or N wherein N is optionally substituted with alkyl, alkenyl, alkynyl being linear or branched;

a phenyl, phenylalkenyl, or phenylalkyl optionally substituted with halogen, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, arylcarboxamido, alkylthio, or haloalkylthio groups being linear or branched;

a heteroaryl, heteroarylalkyl or heteroarylalkenyl wherein the heteroaryl group is a monocyclic five or six membered ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with halogen, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, alkenyl, alkynyl, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, arylcarboxamido, alkylthio or haloalkylthio groups being linear or branched, provided at least one of X or Y is N; and

provided that where both X and Y are N, only one of X or Y is substituted; and

R₁, R₂, R₃, R₄ and R₅ further including any of the structures depicted for this group in FIGS. 3A-1 through 3A-3.

15. An inhibitor according to 14, wherein the warhead moiety is selected from the group consisting of:

a non-oxadiazole heterocycle including benzoxazole and substituted benzoxazole;

perfluorinated alkylketone including trifluoromethyl ketone and pentafluoroethyl ketone;

halomethyl ketone, boronic acid, aldehyde, di-ketone, alpha keto acid, alpha keto ester; and

active ester.

16. A pharmaceutical formulation for treating an elastase induced pathology, comprising:

an effective dose of a compound according to claim 14.

17. A method of inhibiting proteinase-3, comprising:

administering to a subject in need of proteinase-3 inhibition, an effective amount of a compound according to claim 14 in a pharmaceutically acceptable formulation.

18. A method of inhibiting neutrophil elastase, comprising:

administering to a subject in need of neutrophil elastase inhibition, an effective amount of a compound according to claim 14 in a pharmaceutically acceptable formulation.

19. A method according to claim 17, further comprising:

administering to a subject in need of neutrophil elastase and proteinase-3 inhibition, an effective amount of the compound in a pharmaceutically acceptable formulation so as to inhibit both proteinase-3 and neutrophil elastase.