PROGRESS TOWARDS NEW CONFORMATIONALLY CONSTRAINED HIV-1 PROTEASE INHIBITORS

Citation
Z. Benatalah et al., PROGRESS TOWARDS NEW CONFORMATIONALLY CONSTRAINED HIV-1 PROTEASE INHIBITORS, European journal of medicinal chemistry, 30(11), 1995, pp. 891-900
Citations number
28
Categorie Soggetti
Chemistry Medicinal
ISSN journal
02235234
Volume
30
Issue
11
Year of publication
1995
Pages
891 - 900
Database
ISI
SICI code
0223-5234(1995)30:11<891:PTNCCH>2.0.ZU;2-3
Abstract
Two series of molecules containing a trisubstituted cyclopentyl group as the central unit were synthesized and evaluated as inhibitors of HI V-1 protease (HIV PR). In the first series of molecules (13-20), the c entral unit A, 3-(N-acyl)amino-2-hydroxy-1-cyclopentylacetyl, was desi gned so as to reproduce three of the central interactions found in the 'classical' complex HIV PR-JG365 inhibitor. Significant inhibitions ( IC50 similar to 10 mu M) were obtained with compound 20 in which the c entral unit was elongated by Z-Ile-Phe at the N-terminus and by Val-OM e at the C-terminus. In the second series of molecules (21-28), the ce ntral unit B, 3-hydroxy-2-(N-acyl)amino-1-cyclopentylacetyl, was obtai ned in the first steps of the synthesis. Unexpectedly better inhibitio ns were observed with these derivatives (K-i = 2 mu M for compound 28) . Docking and molecular dynamics simulations performed with compound 2 8 into HIV PR suggested that the HIV PR-28 complex should have a struc ture analogous to that of the recently described HIV PR-urea complex.