CCR5 antagonists as anti-HIV-1 agents. Part 2: Synthesis and biological evaluation of N-[3-(4-benzylpiperidin-1-yl)propyl]- N, N′-diphenylureas

Graphic We have previously reported the novel lead compound 1a as a CCR5 antagonist for treatment of HIV-1 infection. SAR studies on incorporating various acyl groups as a replacement for the 5-oxopyrrolidine-3-carbonyl group of the lead structure resulted in the discovery of N-[3-(4-benzylpiperidin-1-yl)propyl]- N, N ′-diphenylurea ( 4a) with significantly improved CCR5 binding affinity. Substitutions (4-Cl, 4e, f; 4-Me, 4i) on the N ′-phenyl ring further increased the binding affinity. Introduction of polar substituents on the phenyl ring of the 4-benzylpiperidine moiety enhanced the inhibitory activity of the HIV-1 envelope-mediated membrane fusion ( 4v, w), suggesting that polar substituents at this position can interfere effectively with HIV-1 cell entry.