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1: Bioorg Med Chem. 2005 Jan 17;13(2):397-416.Click here to read Links

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

Imamura S, Nishikawa Y, Ichikawa T, Hattori T, Matsushita Y, Hashiguchi S, Kanzaki N, Iizawa Y, Baba M, Sugihara Y.

Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. imamura_shin-ichi@takeda.co.jp

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 (EC50=0.59 nM) and an acceptable pharmacokinetic profile in dogs.

PMID: 15598561 [PubMed - indexed for MEDLINE]