Discovery of a piperidine-4-carboxamide CCR5 antagonist (TAK-220) with highly potent Anti-HIV-1 activity

Journal of Medicinal Chemistry
Shinichi ImamuraYoshihiro Sugihara

Abstract

We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC(50) = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl)piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC(50) = 3.5 nM) and potent inhibition of membrane fusion (IC(50) = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC(50) = 1.1 nM, EC(90) = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.

References

Jan 1, 1970·Journal of Medicinal Chemistry·R L DuncanC D Lunsford
Feb 17, 1997·The Journal of Experimental Medicine·R I ConnorN R Landau
May 13, 1999·Proceedings of the National Academy of Sciences of the United States of America·M BabaM Fujino
Jun 8, 1999·Annual Review of Immunology·E A BergerJ M Farber
Jan 8, 2004·Chemical & Pharmaceutical Bulletin·Shinichi ImamuraShohei Hashiguchi
Dec 16, 2004·Bioorganic & Medicinal Chemistry·Shinichi ImamuraYoshihiro Sugihara

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Citations

Jan 18, 2013·Archives of Pharmacal Research·Changdev G GadheSeung Joo Cho
Feb 2, 2010·Nature Reviews. Drug Discovery·Rory R Koenen, Christian Weber
Jul 17, 2014·European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology·W-G Gu, X-Q Chen
May 16, 2009·Expert Opinion on Therapeutic Patents·James E Pease, Richard Horuk
Oct 5, 2013·Expert Opinion on Therapeutic Targets·Rafael Elias MarquesMauro Martins Teixeira
Nov 1, 2008·Expert Opinion on Drug Discovery·Patrick Dorr, Manos Perros
Jun 1, 2012·Expert Opinion on Drug Discovery·Chie HashimotoHirokazu Tamamura
Aug 23, 2008·Medicinal Research Reviews·Keduo QianKuo-Hsiung Lee
May 15, 2015·Cardiovascular Research·Silvano SozzaniMassimo Locati
Feb 7, 2017·Journal of Medicinal Chemistry·Marta ArimontChris de Graaf
Sep 17, 2010·ChemMedChem·Maria HertjeUrsula Dietrich
Sep 9, 2006·Annual Review of Medicine·Athe M N Tsibris, Daniel R Kuritzkes
Dec 22, 2007·Molecular Pharmacology·Rama KondruMarianna Dioszegi
Mar 13, 2013·Protein & Cell·Yuanxi KangZhiwei Chen
Oct 30, 2016·Expert Opinion on Investigational Drugs·Michelle B KimLawrence J Wilson
Aug 27, 2019·Frontiers in Aging Neuroscience·Tianwen Li, Jianhong Zhu
Feb 16, 2020·Medicinal Research Reviews·Xingyue Ji, Zhuorong Li
Oct 20, 2020·Drug Discovery Today·Boshi HuangYan Zhang
Jun 5, 2010·The Journal of Organic Chemistry·Naohiro Fukuda, Tomomi Ikemoto

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