Journal of Medicinal Chemistry 1992-05-29

Renin inhibitors containing C-termini derived from mercaptoheterocycles.

W T Ashton, C L Cantone, L C Meurer, R L Tolman, W J Greenlee, A A Patchett, R J Lynch, T W Schorn, J F Strouse, P K Siegl

Index: J. Med. Chem. 35 , 2103, (1992)

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Abstract

A series of transition-state analogues having heterocyclythio C-termini has been synthesized and evaluated for inhibition of human renin. Addition of mercaptoheterocycles to a chiral Boc-amino epoxide intermediate led, after several steps, to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio derivatives. Oxidation of the thioether to sulfone was also investigated. Several of the compounds, especially those derived from N1-substituted-5-mercaptotetrazoles or N4-substituted-3-mercapto-5-(trifluoromethyl)-1,2,4-triazoles, were moderately potent inhibitors of human plasma renin, having IC50 values of 30-40 nM. When selected compounds were administered intravenously to sodium-deficient rhesus monkeys at 0.3-1.2 mg/kg, they reduced plasma renin activity by 75-98%. However, this inhibition and the accompanying drop in blood pressure were of short duration.