CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological evaluation of piperidine-4-carboxamide derivatives.
Bioorganic & medicinal chemistry 2005 Jan 17; 13(2):397-416
Imamura S S, Nishikawa Y Y, Ichikawa T T, Hattori T T, Matsushita Y Y, Hashiguchi S S, Kanzaki N N, Iizawa Y Y, Baba M M, Sugihara Y 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.