Novel synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline and analogs: potent angiotensin converting enzyme inhibitors

Abstract

A new approach was developed for the synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1) and 23 analogs. The .delta.-(acylamino)-.gamma.-keto acid intermediates were obtained by a modified Dakin-West reaction using 3-carbomethoxypropionyl chloride. Acylation of L-proline and recrystallization of the mixture of diastereomers gave the optically pure 1 in 3 reaction steps. The in vitro angiotensin converting enzyme (ACE) inhibitory activity of 1 was confirmed. Some of the novel analogs were potent inhibitors of ACE in vitro with an IC50 [median inhibitory dose] of 1.4-8.8 .times. 10-9 M (IC50 for captopril = 0.9 x 10-8 M). In vivo these compounds were much less active than captopril, especially by the oral route. Against angiotensin I (AI) challenge in normotenksive conscious rats, 1 and another analog produced < 50% inhibition at 30 mg/kg orally but 57-82% inhibition at 3 mg/kg i.v. Inhibition by both routes lasted < 1 h. In renal hypertensive rats, 1 and 15 of its analogs failed to produce significant blood pressure lowering effects, in contrast to the marked effects of captopril. Near maximum inhibition of AI was achieved by continuous i.v. infusions of 1 and another and log, suggesting that limited oral activity may be due to degradation and/or clearance.