Z. Benatalah et al., PROGRESS TOWARDS NEW CONFORMATIONALLY CONSTRAINED HIV-1 PROTEASE INHIBITORS, European journal of medicinal chemistry, 30(11), 1995, pp. 891-900
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.