Compounds for enzyme inhibition
View Patent ↗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 at least three peptide units, 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.
1. A compound having the formula:
2. A pharmaceutically acceptable salt of a compound having the formula:
3. The pharmaceutically acceptable salt of claim 2 , wherein the pharmaceutically acceptable salt is a citrate salt.
4. A composition comprising a compound having the formula:
or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
5. The composition of claim 4 , wherein the composition comprises a compound having the formula:
and one or more pharmaceutically acceptable carriers.
6. The composition of claim 4 , wherein the composition comprises a pharmaceutically acceptable salt of a compound having the formula:
and one or more pharmaceutically acceptable carriers.
7. The composition of claim 4 , wherein each of the one or more pharmaceutically acceptable carriers is independently selected from a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, a coating agent, a cyclodextrin, and a buffer.
8. The composition of claim 4 , wherein each of the one or more pharmaceutically acceptable carriers is independently selected from:
(1) a sugar selected from lactose, glucose, and sucrose; (2) a starch selected from corn starch, potato starch, and substituted or unsubstituted (3-cyclodextrin; (3) cellulose or a derivative selected from sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) an excipient selected from cocoa butter and suppository waxes; (9) an oil selected from peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) propylene glycol; (11) a polyol selected from glycerin, sorbitol, mannitol, and polyethylene glycol; (12) an ester selected from ethyl oleate and ethyl laurate; (13) agar; (14) a buffering agent selected from magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
9. The composition of claim 4 , wherein at least one of the one or more pharmaceutically acceptable carriers is a cyclodextrin.
10. The composition of claim 4 , wherein at least one of the one or more pharmaceutically acceptable carriers is a substituted or unsubstituted (3-cyclodextrin.
11. The composition of claim 4 , wherein at least one of the one or more pharmaceutically acceptable carriers is a buffer.
12. The composition of claim 4 , wherein the composition further comprises an anti-oxidant.
13. The composition of claim 12 , wherein the anti-oxidant is citric acid.
14. The composition of claim 4 , wherein the composition further comprises one or more other therapeutic agents.
15. The composition of claim 14 , wherein at least one of the one or more other therapeutic agents is a chemotherapeutic agent.
16. The composition of claim 4 , wherein the composition is in a form suitable for intravenous administration.
17. The composition of claim 4 , wherein the compound or salt is in hydrated form.
18. The composition of claim 4 , wherein the composition is in a solid form that is suitable for reconstitution in a sterile injectable medium.
19. A composition comprising:
(i) a compound having the formula:
or a pharmaceutically acceptable salt thereof; and
(ii) water.
20. The composition of claim 19 , wherein the water is sterile water.
21. The composition of claim 19 , wherein the composition further comprises one or more other pharmaceutically acceptable carriers.
22. The composition of claim 21 , wherein each of the one or more other pharmaceutically acceptable carriers is independently selected from a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, a coating agent, a cyclodextrin, and a buffer.
23. The composition of claim 21 , wherein each of the one or more other pharmaceutically acceptable carriers is each independently selected from:
(1) a sugar selected from lactose, glucose, and sucrose; (2) a starch selected from corn starch, potato starch, and substituted or unsubstituted 3-cyclodextrin; (3) cellulose or a derivative selected from sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) an excipient selected from cocoa butter and suppository waxes; (9) an oil selected from peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) propylene glycol; (11) a polyol selected from glycerin, sorbitol, mannitol, and polyethylene glycol; (12) an ester selected from ethyl oleate and ethyl laurate; (13) agar; (14) a buffering agent selected from magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
24. The composition of claim 21 , wherein at least one of the one or more other pharmaceutically acceptable carriers is a cyclodextrin.
25. The composition of claim 21 , wherein at least one of the one or more other pharmaceutically acceptable carriers is a substituted or unsubstituted 3-cyclodextrin.
26. The composition of claim 21 , wherein at least one of the one or more other pharmaceutically acceptable carriers is a buffer.
27. The composition of claim 19 , wherein the composition further comprises an anti-oxidant.
28. The composition of claim 27 , wherein the anti-oxidant is citric acid.
29. The composition of claim 19 , wherein the composition is in the form of an aqueous solution, dispersion, suspension or emulsion.
30. The composition of claim 19 , wherein the composition is in a form suitable for intravenous administration.