Studies on Angiotensin Converting Enzyme Inhibitors. III. 2-Carboxyethylcarbamoyl-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic Acid Derivatives

Abstract

(3S)-2-[N-Substituted N-(2-carboxyethyl) carbamoyl]-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid derivaties (8a-d and 12a-t) and their monoester compounds (13a-k) were synthesized by condensation of (3S)-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylates (6a, b), 3-aminopropionates (5a, b or 10a-m) and phosgene, followed by deprotection of ester groups. Their in vitro angiotensin converting enzyme (ACE) inhibitory activities and antihypertensive effects were evaluated, and the structure-activity relationship is discussed. Some of the N-ethylcarbamoyl analogs (12h, 12j, 12k, 12l and 12o), which had hydrophobic substituents (C₈H₁₇-C₁₂H₂₅, CH₂CH₂Ph) at the α-position to the carboxyl group in the side chain, showed potent in vitro ACE inhibitory activities with IC₅₀ values of 4.0-8.8×10^-9M. The monoesters 13e, 13h, and 13i reduced the systolic blood pressure by more than 30 mmHg in spontaneously hypertensive rats (SHR) at an oral dose of 50mg/kg.