Claims for Patent: 7,417,042

Summary for Patent: 7,417,042

Title:	Compounds for enzyme inhibition
Abstract:	Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.
Inventor(s):	Smyth; Mark S. (Foster City, CA), Laidig; Guy J. (Menlo Park, CA)
Assignee:	Proteolix, Inc. (South San Francisco, CA)
Application Number:	11/199,899
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,417,042
Patent Claims:	1. A compound having a structure of formula I or a pharmaceutically acceptable salt thereof, ##STR00024## wherein X is O, NH, or N-alkyl; Y is NH, N-alkyl, O, or C(R.sup.9).sub.2; Z is O or C(R.sup.9).sub.2; R.sub.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; each R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from alkyl, amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; m is an integer from 0 to 2; and n is an integer from 0 to 2. 2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O. 3. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, and C.sub.1-6aralkyl; and R.sup.9 is hydrogen. 4. A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.7 are independently C.sub.1-6aralkyl and R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl. 5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is selected from N-alkyl, O, and CH.sub.2. 6. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is CH.sub.2, and m and n are both 0. 7. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is CH.sub.2, m is 0, and n is 2. 8. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is O, m is 1, and n is 2. 9. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the following structure ##STR00025## 10. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the following structure ##STR00026## 11. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure ##STR00027## 12. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure ##STR00028## 13. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure ##STR00029## 14. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure ##STR00030## 15. A compound of claim 1, having a structure of formula III or a pharmaceutically acceptable salt thereof, ##STR00031## wherein X is selected from O, NH, and N-alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; and R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether. 16. A compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein X is O. 17. A compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6 hydroxyalkyl, and C.sub.1-6aralkyl. 18. A compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.7 are independently C.sub.1-6aralkyl and R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl. 19. A compound of claim 1, having a structure of formula IV or a pharmaceutically acceptable salt thereof, ##STR00032## wherein X is O, NH, or N-alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; and R.sup.6 and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether. 20. A compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein X is O. 21. A compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, and C.sub.1-6aralkyl. 22. A compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl. 23. A compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are both isobutyl. 24. A compound of claim 19 or a pharmaceutically acceptable salt thereof, having the following structure ##STR00033## 25. A compound of claim 1, having a structure of formula V or a pharmaceutically acceptable salt thereof, ##STR00034## where X is O, NH, or N-alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; and q is an integer from 0 to 3. 26. A compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein X is O. 27. A compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, and C.sub.1-6aralkyl. 28. A compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.7 are independently C.sub.1-6aralkyl and R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl. 29. A compound of claim 1, having a structure of formula VI or a pharmaceutically acceptable salt thereof, ##STR00035## wherein X is O, NH, or N-alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; R.sup.6 and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; and q is an integer from 0 to 3. 30. A compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein X is O. 31. A compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, and C.sub.1-6aralkyl. 32. A compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl. 33. A compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are both isobutyl. 34. A compound of claim 29 or a pharmaceutically acceptable salt thereof, having the structure ##STR00036## 35. A compound of claim 29 or a pharmaceutically acceptable salt thereof, having the structure ##STR00037## 36. A compound of claim 29 or a pharmaceutically acceptable salt thereof, having the following structure ##STR00038## 37. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.