Angiotensin converting enzyme inhibitors: N-Substituted monocyclic and bicyclic amino acid derivatives

Abstract

The synthesis of N-(3-mercaptopropionyl)-N-arylglycines, -N-arylalanines, -N-cycloalkylglycines and -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids, -1,2,3,4-tetrahydroquinoline-2-carboxylic acids and -indoline-2-carboxylic acids is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound, and the structure-activity relationship for each series is discussed. The in vivo inhibition of ACE and antihypertensive effects of representative compounds from each series are discussed. The most potent compound, 1-[3-mercapto-2(S)-methylpropionyl]indoline-2(S)-carboxylic acid, had an in vitro ACE IC50 [median inhibitory concentration] of 2.6 .times. 10-9 M and lowered blood pressure in spontaneous hypertensive rats 85 mm at an oral dose of 10 mg/kg.