Evaluation of a potent inhibitor of subprimate and primate renins

Our attempts to synthesize a potent inhibitor of rat renin have resulted in the discovery of CGP 44 099 A, a potent inhibitor of plasma renin from all subprimate species tested so far [IC50 (in nM): dog, 0.007; rabbit, 0.033; guinea pig, 0.34; mouse, 0.4; cat, 0.57; and rat, 1.3]. This compound is also a potent inhibitor of primate renins [IC50 (in nM): human, 0.3; and marmoset, 1.4]. It is less potent against other aspartic proteinases [IC50 (in nM): porcine pepsin, 26; and bovine cathepsin D, 230). CGP 44 099 A exhibited a competitive mode of inhibition against human renin (Ki, 0.12 nM). During i.v. infusion of CGP 44 099 A in sodium-depleted normotensive rats (0.1 mg/kg/min) blood pressure (BP) was lowered by about 25 mm Hg. Plasma renin activity, angiotensin I and angiotensin II were almost completely suppressed. The converting enzyme inhibitor enalaprilat (1 mg/kg i.v.) also lowered BP by about 25 mm Hg. No further fall in BP occurred when CGP 44 099 A (0.1 mg/kg/min) was infused after pretreatment with enalaprilat (1 mg/kg i.v.) and CGP 44 099 A did not lower BP when infused in bilaterally nephrectomized rats. These results indicate that the hypotensive response induced by CGP 44 099 A in sodium-depleted rats is specifically due to the renin inhibition. Compounds such as CGP 44 099 may therefore be useful for comparing the effects of renin inhibition in different species and for studying the role of renin in various models of cardiovascular disease in nonprimate species.