STUDIES DIRECTED TOWARD THE DESIGN OF ORALLY ACTIVE RENIN INHIBITORS .2. DEVELOPMENT OF THE EFFICACIOUS, BIOAVAILABLE RENIN INHIBITOR (2S)-2-BENZYL-3-[[(1-METHYLPIPERAZIN-4-YL)SULFONYL]PROPIONYL]-3-THIAZOL-4-YL-L-ALANINE AMIDE OF (2S,3R,4S)-2-AMINO-1-CYCLOHEXYL-3,4-DIHYDROXY-6-METHYLHEPTANE (A-72517)

Employing a set of empirical guidelines for the design of well-absorbed renin inhibitors, we have followed two strategies to improve potency while maintaining bioavailability. One process involved incorporation of an extended N-terminal residue bearing a weakly basic substituent and is exemplified by compound 25. The other approach centered on the inclusion of an N-terminal sulfonamide and culminated in the discovery of inhibitor 32 (A-72517). Both 25 and 32 showed excellent bioavailability in the rat and ferret (> 25 %) and, while subject to hepatic elimination in the monkey, were efficacious in this species.