Conformationally restricted inhibitors of angiotensin converting enzyme: synthesis and computations.
J Med Chem
; 29(2): 251-60, 1986 Feb.
Article
en En
| MEDLINE
| ID: mdl-3005569
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores de la Enzima Convertidora de Angiotensina
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1986
Tipo del documento:
Article
Pais de publicación:
Estados Unidos