Discovery of INCB9471, a Potent, Selective, and Orally Bioavailable CCR5 Antagonist with Potent Anti-HIV-1 Activity

  • ACS Med Chem Lett. 2010 Aug 25;1(9):483-7. doi: 10.1021/ml1001536.
Chu-Biao Xue  1 ,  Lihua Chen  1 ,  Ganfeng Cao  1 ,  Ke Zhang  1 ,  Anlai Wang  1 ,  David Meloni  1 ,  Joseph Glenn  1 ,  Rajan Anand  1 ,  Michael Xia  1 ,  Ling Kong  1 ,  Taisheng Huang  1 ,  Hao Feng  1 ,  Changsheng Zheng  1 ,  Mei Li  1 ,  Laurine Galya  1 ,  Jiacheng Zhou  1 ,  Niu Shin  1 ,  Fredric Baribaud  1 ,  Kim Solomon  1 ,  Peggy Scherle  1 ,  Bitao Zhao  1 ,  Sharon Diamond  1 ,  Tom Emm  1 ,  Douglas Keller  1 ,  Nancy Contel  1 ,  Swamy Yeleswaram  1 ,  Kris Vaddi  1 ,  Gregory Hollis  1 ,  Robert Newton  1 ,  Steven Friedman  1 ,  Brian Metcalf  1
Affiliations
  • 1. Incyte Corporation, Experimental Station E336, Wilmington, Delaware 19880.
PMID: 24900235 DOI: 10.1021/ml1001536
Abstract

To identify a CCR5 Antagonist as an HIV-1 entry inhibitor, we designed a novel series of indane derivatives based on conformational considerations. Modification on the indane ring led to the discovery of compound 22a (INCB9471) that exhibited high affinity for CCR5, potent anti-HIV-1 activity, high receptor selectivity, excellent oral bioavailability, and a tolerated safety profile. INCB9471 has entered human clinical trials.

Keywords
CCR5; HIV-1; antagonist; antiviral; coreceptor.
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