4-Fluoro-Thio-containing inhibitors of APP2, compositions thereof and method of use

摘要

The present invention has multiple aspects. In its first aspect, it is directed to a compound that is a 4(S)-fluoro-thio-tripeptide analog that has the unexpectedly superior property of specifically inhibiting the enzyme, membrane-bound aminopeptidase P2 (APP2), whose natural substrate is bradykinin, but not the enzyme angiotensin converting enzyme (ACE) which also cleaves bradykinin. In its second aspect, the present invention is directed to a pharmaceutical composition comprising the 4(S)-fluoro-thio-tripeptide analog and a pharmaceutically acceptable carrier. In its third aspect, the invention is directed to a method of inhibiting bradykinin degradation in a mammalian patient, comprising administering a therapeutically effective amount of the compound of the invention to a mammalian patient in need of inhibition of bradykinin degradation.

主权项

1. A compound according to the formula: wherein R1 is H or R3—(CO)—; wherein R2 is H; alkyl or substituted alkyl, having from 1 to 6 carbon atoms; or cycloalkyl-(CH2)a—, aryl-(CH2)a—, substituted aryl-(CH2)a—, or heteroaryl-(CH2)a—, having from 4 to 12 carbon atoms wherein R3 is alkyl or substituted alkyl, having 1-6 carbon atoms; or cycloalkyl-(CH2)a—, aryl-(CH2)a—, substituted aryl-(CH2)a—, or heteroaryl-(CH2)a—, having from 4 to 12 carbon atoms; a is zero or an integer from 1 to 6; or a pharmaceutically acceptable salt thereof.