1,2,4-TRIAZOLO[4,3-A]PYRAZINE DERIVATIVES WITH HUMAN RENIN INHIBITORY ACTIVITY .2. SYNTHESIS, BIOLOGICAL PROPERTIES AND MOLECULAR MODELING OF HYDROXYETHYLENE ISOSTERE DERIVATIVES

A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-l,2,4-triazolo[4,3-α]pyrazin-3-yl)-3-pyridin-3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (Cha--°H Val), The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2’ sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50s < 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing. © 1990, American Chemical Society. All rights reserved.