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 heme-related malignancy 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 selected from the group consisting of isoxazole, isothiazole, furan, thiophene, oxazole, thiazole, pyrazole, and imidazole; 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;
a steroid; and
a nitrogen mustard alkylating agent.
2. The method of claim 1 , wherein the steroid is selected from the group consisting of: 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, ditlucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, fonnocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts thereof.
3. The method of claim 2 , wherein the steroid is dexamethasone.
4. The method of claim 1 , wherein the nitrogen mustard alkylating agent is selected from the group consisting of: mechlorethamine, cyclophosphamide, melphalan, and chlorambucil.
5. The method of claim 4 , wherein the nitrogen mustard alkylating agent is melphalan.
6. The method of claim 4 , wherein the nitrogen mustard alkylating agent is cyclophosphamide.
7. The method of claim 1 , wherein the steroid is dexamethasone and the nitrogen mustard alkylating agent is melphalan.
8. The method of claim 1 , wherein the steroid is dexamethasone and the nitrogen mustard alkylating agent is cyclophosamide.
9. The method of claim 1 , wherein Z is absent.
10. The method of claim 1 , wherein R 4 , R 6 , and R 7 are independently selected from hydrogen and methyl.
11. The method of claim 1 , wherein L is C═O.
12. 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.
13. The method of claim 12 , wherein any of R 1 , R 2 , and R 3 are independently C 1-6 alkyl.
14. The method of claim 13 , wherein any of R 1 , R 2 , and R 3 are independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and isobutyl.
15. The method of claim 12 , wherein any of R 1 , R 2 , and R 3 are independently propargyl.
16. The method of claim 12 , wherein any of R 1 , R 2 , and R 3 are independently C 1-6 hydroxyalkyl.
17. The method of claim 16 , wherein any of R 1 , R 2 , and R 3 are independently selected from hydroxymethyl and hydroxyethyl.
18. The method of claim 12 , wherein any of R 1 , R 2 , and R 3 are independently C 1-6 alkoxyalkyl.
19. The method of claim 18 , wherein any of R 1 , R 2 , and R 3 are independently selected from methoxymethyl and methoxyethyl.
20. The method of claim 12 , wherein any of R 1 , R 2 , and R 3 are independently C 1-6 heteroaralkyl.
21. The method of claim 20 , wherein any of R 1 , R 2 , and R 3 are independently selected from imidazolylmethyl, pyrazolylmethyl, and thiazolylmethyl, and pyridylmethyl.
22. The method of claim 12 , wherein any of R 1 , R 2 , and R 3 are independently cyclohexylmethyl.
23. The method of claim 1 , wherein R 1 , R 2 , and R 3 are all different.
24. 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.
25. The method of claim 24 , wherein at least one of R 1 and R 2 is C 1-6 alkoxyalkyl.
26. The method of claim 25 , wherein at least one of R 1 and R 2 is selected from methoxymethyl and methoxyethyl.
27. The method of claim 26 , wherein R 3 is selected from C 1-6 alkyl and C 1-6 aralkyl.
28. The method of claim 27 , wherein R 3 is C 1-6 alkyl.
29. The method of claim 28 , wherein R 3 is selected from methyl, ethyl, isopropyl, sec-butyl, and isobutyl.
30. The method of claim 29 , wherein R 3 is isobutyl.
31. The method of claim 29 , wherein R 3 is C 1-6 aralkyl.
32. The method of claim 31 , wherein R 3 is phenylmethyl.
33. The method of claim 1 , wherein R 5 is selected from isoxazole, furan, or thiophene.
34. The method of claim 33 , wherein R 5 is furan or thiophene.
35. The method of claim 1 , wherein R 5 is thiazole.
36. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
37. The method of claim 1 , wherein the pharmaceutical composition is orally bioavailable.
38. The method of claim 1 , wherein the heme-related malignancy is multiple myeloma.
39. A method for treating a heme-related malignancy 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;
a steroid; and
an immunotherapeutic agent.
40. The method of claim 39 , wherein the steroid is selected from the group consisting of: 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, ditlucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, fonnocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts thereof.
41. The method of claim 40 , wherein the steroid is dexamethasone.
42. The method of claim 39 , wherein the nitrogen mustard alkylating agent is selected from the group consisting of: mechlorethamine, cyclophosphamide, melphalan, and chlorambucil.
43. The method of claim 42 , wherein the nitrogen mustard alkylating agent is melphalan.
44. The method of claim 42 , wherein the nitrogen mustard alkylating agent is cyclophosphamide.
45. The method of claim 39 , wherein the steroid is dexamethasone and the nitrogen mustard alkylating agent is melphalan.
46. The method of claim 39 , wherein the steroid is dexamethasone and the nitrogen mustard alkylating agent is cyclophosamide.
47. The method of claim 39 , wherein the pharmaceutical composition is orally bioavailable.
48. The method of claim 39 , wherein the heme-related malignancy is multiple myeloma.