New inhibitors of human renin that contain novel Leu-Val replacements.

Stereoselective syntheses of several nonpeptide fragments that function as Leu10-Val11 scissile bond replacements in human angiotensinogen are presented. The opening of N-protected aminoalkyl epoxide 3 with a variety of sulfur, oxygen, nitrogen, and carbon nucleophiles is a key reaction in the preparation of these novel fragments 4-8. The coupling of these fragments to protected dipeptides that mimic positions 8 and 9 in angiotensinogen produces inhibitors of human renin even though the molecules contain no functionality beyond what is formally the Val11 side chain of angiotensinogen. R groups that closely resemble that of the Val side chain are preferable; thus, isopropyl greater than or equal to higher alkyl greater than phenyl greater than substituted phenyl. Sulfur is the best X group; oxidation leads to slight (X = SO2) and significant (X = SO) decreases in inhibitory potency. One such inhibitor, 60, has an IC50 of 13 nM when tested with purified human renin at pH 6.0. The significant activity of these small inhibitors is thought to be due in part to the hydroxyl group of the fragment functioning as a transition-state analogue. Of these, the inhibitors that contain histidine show marked selectivity toward renin over a related aspartic proteinase, pepsin.