Structure and conformation of a novel inhibitor of angiotensin I converting enzyme – a tripeptide containing phosphonic acid

Abstract

A novel phosphotripeptide, (IR)-1-(N-(N-acetyl-L-isoleucyl)-L-tyrosyl)amino-2-(4-hydroxyphenyl)ethy l- phosphonic acid, is a potent inhibitor of angiotensin I converting enzyme (ACE). ACE inhibitory activity in vitro of the peptide is comparable to that of captopril. Its diethylester (C29H42N3O8P, molecular weight, 591.6) crystallizes in the monoclinic space group C2, with cell constants: a = 25.666(9), b = 9.590(8), c = 13.557(2)A, beta = 91.65(2) degrees, Z = 4, Dc = 1.17 g/cm3. The structure was solved by MULTAN 11/82 and refined by full matrix least-squares methods to a final R-factor of 0.063 for 2123 unique reflections (F greater than 3 sigma(F] measured on an Enraf-Nonius CAD-4 diffractometer (CuK alpha, lambda = 1.541 8 A, T = 295 K). The absolute configuration of the alpha-carbon where the phosphonic acid is attached was determined unequivocally by referring to the L-isoleucyl moiety whose absolute configuration is known. The conformation of the molecule is relatively rigid owing to the intramolecular requisites and the resultant relative disposition of hetero atoms, which are necessary to its biological activities, are confined to the corresponding disposition in captopril.