Structure-activity relationships of HIV-1 PR inhibitors containing AHPBA .2. Modification of pyrrolidine ring at P1' proline

Systematic replacement in the 3- or 4-position of the pyrrolidine ring at P1' proline was carried out. Compound 26, which has a C1 atom in the 4(S)-position was the most active among inhibitors substituted with other halogen atoms or other substituents. Furthermore, the replacement of the Z group in compound 26 with five- or six-membered fused aromatic heterocycle carbonyl groups produced more potent inhibitors. 7-Methoxybenzofuran-2-carbonyl derivative (44) was the best of these and showed K-i = 4.5 nM against HIV PR and IC(50)s 0.58 mu M and 0.06 mu M in chronic and acute infections, respectively. These results suggest that the combination of the 4(S)-Cl atom and fused bicyclic heterocycles may be effective in improving their cellular penetration. Copyright (C) 1996 Elsevier Science Ltd