Conformationally restricted inhibitors of angiotensin converting enzyme: synthesis and computations.
Basic Information
ID: ALA1123398
Journal: J Med Chem
Title: Conformationally restricted inhibitors of angiotensin converting enzyme: synthesis and computations.
Authors: Thorsett ED, Harris EE, Aster SD, Peterson ER, Snyder JP, Springer JP, Hirshfield J, Tristram EW, Patchett AA, Ulm EH.
Abstract: A series of inhibitors of angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase, EC 3.4.15.1) is described which addresses certain conformational aspects of the enzyme-inhibitor interaction. In this study the alanylproline portion of the potent ACE inhibitor enalaprilat (2) is replaced by a series of monocyclic lactams containing the required recognition and binding elements. In order to more fully assess the lactam ring conformations and the key backbone angle psi as defined in 3 with respect to possible enzyme-bound conformations, a series of model lactams was investigated with use of molecular mechanics. The results point to a correlation between inhibitor potency (IC50) and the computed psi angle for the lowest energy conformation of the model compounds. Thus the psi angle as defined in 3 is an important determinant in the binding of inhibitors to ACE. The inhibition data in conjunction with the computational data have served to define a window of psi angles from 130 degrees to 170 degrees which seems to be acceptable to the ACE active site.
CiteXplore: 3005569
DOI: 10.1021/jm00152a014
Patent ID: ┄