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 a solid tumor 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 5 , 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 23 , 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 27 , wherein R 5 is thiazole.
31. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
32. The method of claim 1 , wherein the pharmaceutical composition is orally bioavailable.
33. A method for treating a solid tumor 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.
34. The method of claim 33 , wherein the pharmaceutical composition is orally bioavailable.