DESIGN AND SYNTHESIS OF NONPEPTIDE PEPTIDOMIMETIC INHIBITORS OF RENIN

The desire to replace the amide backbone of renin inhibitors with a ne w scaffold led us to explore vinylogous amides (enaminones). An initia l attempt proved unsuccessful, a result explained after the fact via d ocking experiments. Based on this lesson, we designed a different viny logous amide scaffold which incorporated one or more pyrrolinone rings into the backbone. Three of the four compounds gave IC(50)s in the 0. 6 to 18 mu M range. These compounds did not inhibit HIV-1 protease. Ta ken together, the results reported herein provide insights into the ro le of hydrogen bonding and steric interactions for binding to renin. ( C) 1994 John Wiley & Sons, Inc.