Pharmacology of novel imidazole alcohol inhibitors of primate renin


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Abstract

SQ 30774 and SQ 31 844 are representatives of a novel class of renin inhibitors, the imidazole alcohols. These compounds, which contain an imidazole ring as part of their active site binding group are potent in vitro inhibitors of primate renin, but not rat, hog or dog renin. In conscious, sodium-depleted cynomolgus monkeys both compounds produced a dose-related inhibition of plasma renin activity (PRA) at doses ranging between 0.001 and 1.0μmol/kg, intravenously, and total inhibition was observed after the highest dose. However, a reduction in blood pressure was observed only after an intravenous dose of 10μmol/kg or when the compounds were administered by infusion. In sodium-replete monkeys, SQ 30774 inhibited the rise in arterial pressure and PRA following administration of exogenous monkey renin. When the compounds were administered orally at 50μmol/kg, only SQ 31 844 significantly inhibited PRA (80%). It is concluded that representatives of the imidazole alcohol class of renin inhibitors are potent inhibitors of renin in vitro and inhibit PRA and lower arterial pressure in vivo.

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