DESIGN AND SYNTHESIS OF NONPEPTIDE PEPTIDOMIMETIC INHIBITORS OF RENIN

The desire to replace the amide backbone of renin inhibitors with a new scaffold led us to explore vinylogous amides (enaminones). An initial attempt proved unsuccessful, a result explained after the fact via docking experiments. Based on this lesson, we designed a different vinylogous 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. Taken together, the results reported herein provide insights into the role of hydrogen bonding and steric interactions for binding to renin. (C) 1994 John Wiley & Sons, Inc.