CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological evaluation of piperidine-4-carboxamide derivatives

2005 
Abstract Replacement of the 5-oxopyrrolidin-3-yl fragment in the previously reported lead structure with a 1-acetylpiperidin-4-yl group led to the discovery of a novel series of potent CCR5 antagonists. Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists. The selected compound 11f showed excellent antiviral activity against CCR5-using HIV-1 replication in human peripheral blood mononuclear cells (EC 50  = 0.59 nM) and an acceptable pharmacokinetic profile in dogs.
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