COMPOUNDS FOR ENZYME INHIBITION
Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases associated with the proteasome. 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. Oral administration of these peptide-based proteasome inhibitors is possible due to their bioavailability profiles.
1 . A method for the treatment of an immune-related condition in a patient, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof:
wherein
L is selected from C═O and C═S;
X is selected from O, S, NH, and N—C 1-6 alkyl;
Z is absent, C 1-6 alkyl, or C 1-6 alkoxy;
R 1 , R 2 , and R 3 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, C 1-6 aralkyl, heteroaryl, heterocyclyl, C 1-6 heterocycloalkyl, C 1-6 heteroaralkyl, carbocyclyl, and C 1-6 carbocyclolalkyl;
R 4 is selected from hydrogen, C 1-6 aralkyl, and C 1-6 alkyl;
R 5 is heteroaryl; and
R 6 and R 7 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl and a pharmaceutically acceptable diluent or carrier.
2 . The method of claim 1 , wherein Z is absent.
3 . The method of claim 1 , wherein R 4 , R 6 , and R 7 are independently selected from hydrogen and methyl.
4 . The method of claim 1 , wherein L is C═O.
5 . The method of claim 1 , wherein R 1 , R 2 , and R 3 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 aralkyl, C 1-6 heterocycloalkyl, C 1-6 heteroaralkyl, and C 1-6 carbocyclolalkyl.
6 . The method of claim 5 , wherein any of R 1 , R 2 , and R 3 are independently C 1-6 alkyl.
7 . The method of claim 6 , wherein any of R 1 , R 2 , and R 3 are independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and isobutyl.
8 . The method of claim 7 , wherein any of R 1 , R 2 , and R 3 are independently propargyl.
9 . The method of claim 5 , wherein any of R 1 , R 2 , and R 3 are independently C 1-6 hydroxyalkyl.
10 . The method of claim 9 , wherein any of R 1 , R 2 , and R 3 are independently selected from hydroxymethyl and hydroxyethyl.
11 . The method of claim 5 , wherein any of R 1 , R 2 , and R 3 are independently C 1-6 alkoxyalkyl.
12 . The method of claim 11 , wherein any of R 1 , R 2 , and R 3 are independently selected from methoxymethyl and methoxyethyl.
13 . The method of claim 5 , wherein any of R 1 , R 2 , and R 3 are independently C 1-6 heteroaralkyl.
14 . The method of claim 13 , wherein any of R 1 , R 2 , and R 3 are independently selected from imidazolylmethyl, pyrazolylmethyl, and thiazolylmethyl, and pyridylmethyl.
15 . The method of claim 5 , wherein any of R 1 , R 2 , and R 3 are independently cyclohexylmethyl.
16 . The method of claim 1 , wherein R 1 , R 2 , and R 3 are all different.
17 . The method of claim 1 , wherein at least one of R 1 and R 2 is selected from C 1-6 hydroxyalkyl and C 1-6 alkoxyalkyl.
18 . The method of claim 17 , wherein at least one of R 1 and R 2 is C 1-6 alkoxyalkyl.
19 . The method of claim 18 , wherein at least one of R 1 and R 2 is selected from methoxymethyl and methoxyethyl.
20 . The method of claim 19 , wherein R 3 is selected from C 1-6 alkyl and C 1-6 aralkyl.
21 . The method of claim 20 , wherein R 3 is C 1-6 alkyl.
22 . The method of claim 21 , wherein R 3 is selected from methyl, ethyl, isopropyl, sec-butyl, and isobutyl.
23 . The method of claim 22 , wherein R 3 is isobutyl.
24 . The method of claim 20 , wherein R 3 is C 1-6 aralkyl.
25 . The method of claim 24 , wherein R 3 is phenylmethyl.
26 . The method of claim 1 , wherein R 5 is 5- or 6-membered heteroaryl.
27 . The method of claim 26 , wherein R 5 is selected from isoxazole, isothiazole, furan, thiophene, oxazole, thiazole, pyrazole, or imidazole.
28 . The method of claim 27 , wherein R 5 is selected from isoxazole, furan, or thiophene.
29 . The method of claim 28 , wherein R 5 is furan or thiophene.
30 . The method of claim 29 , wherein R 5 is unsubstituted furan-3-yl or thien-2-yl.
31 . The method of claim 28 , wherein R 5 is isoxazol-3-yl or isoxazol-5-yl.
32 . The method of claim 31 , wherein R 5 is isoxazol-3-yl that has a substituent at the 5-position.
33 . The method of claim 31 , wherein R 5 is isoxazol-5-yl that has a substituent at the 3-position.
34 . The method of claim 32 or 33 , wherein the substituent is selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkyl, carboxylic acid, aminocarboxylate, C 1-6 alkylaminocarboxylate, (C 1-6 alkyl) 2 aminocarboxylate, C 1-6 alkylcarboxylate, C 1-6 heteroaralkyl, C 1-6 aralkyl, C 1-6 heterocycloalkyl, and C 1-6 carbocycloalkyl.
35 . The method of claim 34 , wherein the substituent is selected from methyl, ethyl, isopropyl, and cyclopropylmethyl.
36 . The method of claim 32 or 33 , wherein the substituent is selected from C 1-6 heteroaralkyl and C 1-6 heterocycloalkyl.
37 . The method of claim 36 , wherein the substituent is 1,2,4-triazol-5-ylmethyl.
38 . The method of claim 36 , wherein the substituent is azetidin-1-ylmethyl.
39 . The method of claim 36 , wherein the substituent is
wherein W is O, NR, or CH 2 , and R is H or C 1-6 alkyl.
40 . The method of claim 39 , wherein W is O.
41 . The method of claim 32 or 33 , wherein the substituent is selected from C 1-6 alkoxy and C 1-6 alkoxyalkyl.
42 . The method of claim 41 , wherein the substituent is selected from methoxy, ethoxy, methoxymethy, and methoxyethyl.
43 . The method of claim 32 or 33 , wherein the substituent is selected from carboxylic acid, aminocarboxylate, C 1-6 alkylaminocarboxylate, (C 1-6 alkyl) 2 aminocarboxylate, or C 1-6 alkylcarboxylate.
44 . The method of claim 43 , wherein the substituent is methyl carboxylate.
45 . The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
46 . The method of claim 1 , wherein the immune-related condition is selected from the group consisting of: allergy, asthma, graft-versus-host disease, and an auto-immune disease.
47 . The method of claim 46 , wherein the immune-related condition is graft-versus-host disease.
48 . The method of claim 1 , wherein the method further comprises administration of one or more other proteasome inhibitor(s).
49 . The method of claim 48 , wherein at least one of the one or more other proteasome inhibitor(s) is bortezomib.
50 . The method of claim 1 , wherein the pharmaceutical composition is orally bioavailable.
51 . A method for treating an immune-related condition in a patient comprising administering to the patient a pharmaceutical composition comprising a compound having the structure:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
52 . The method of claim 51 , wherein the pharmaceutical composition is orally bioavailable.
53 . The method of claim 51 , wherein the immune-related condition is selected from the group consisting of: allergy, asthma, graft-versus-host disease, and an auto-immune disease.
54 . The method of claim 53 , wherein the immune-related condition is graft-versus-host disease.
55 . The method of claim 51 , wherein the method further comprises administration of one or more other proteasome inhibitor(s).
56 . The method of claim 55 , wherein at least one of the one or more other proteasome inhibitor(s) is bortezomib.