NONPEPTIDE RENIN INHIBITORS CONTAINING 2-(((3-PHENYLPROPYL)PHOSPHORYL)OXY)ALKANOIC ACID MOIETIES AS P-2-P-3 REPLACEMENTS

A series of novel renin inhibitors containing 2-(((3-phenylpropyl)phos phoryl)oxy) alkanoic acid moieties as P-2-P-3 surrogates are presented . The P-2-P-3 mimetics were obtained from (omega-phenylalkyl)phosphini c acids la-c and 2-hydroxyalkanoic acid benzyl esters 2a-f by N,N'-dic yclohexylcarbodiimide-mediated coupling and subsequent oxidation with sodium metaperjodate. Ester cleavage of these derivatives and coupling with P-1-P-1' transition-state mimetics I-VII provided highly selecti ve compounds with inhibitory potencies in the lower nanomolar range. S mall renin inhibitors, such as analogues 8c and 8h with molecular weig hts of 539 and 537, respectively, could be prepared. These compounds e xhibited IC50 values of about 20 nM against human plasma renin. Compou nd 7i was examined in vivo for its hypotensive effect. In salt-deplete d cynomolgus monkeys, 7i inhibited plasma renin activity almost comple tely and lowered blood pressure after oral administration of a dose of 30 mg/kg.