Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist

  • ACS Med Chem Lett. 2011 Mar 31;2(6):450-4. doi: 10.1021/ml200030q.
Chu-Biao Xue  1 ,  Hao Feng  1 ,  Ganfeng Cao  1 ,  Taisheng Huang  1 ,  Joseph Glenn  1 ,  Rajan Anand  1 ,  David Meloni  1 ,  Ke Zhang  1 ,  Lingquan Kong  1 ,  Anlai Wang  1 ,  Yingxin Zhang  1 ,  Changsheng Zheng  1 ,  Michael Xia  1 ,  Lihua Chen  1 ,  Hiroyuki Tanaka  1 ,  Qi Han  1 ,  D J Robinson  1 ,  Dilip Modi  1 ,  Lou Storace  1 ,  Lixin Shao  1 ,  Vaqar Sharief  1 ,  Mei Li  1 ,  Laurine G Galya  1 ,  Maryanne Covington  1 ,  Peggy Scherle  1 ,  Sharon Diamond  1 ,  Tom Emm  1 ,  Swamy Yeleswaram  1 ,  Nancy Contel  1 ,  Kris Vaddi  1 ,  Robert Newton  1 ,  Greg Hollis  1 ,  Steven Friedman  1 ,  Brian Metcalf  1
Affiliations
  • 1. Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
PMID: 24900329 DOI: 10.1021/ml200030q
Abstract

We report the identification of 13 (INCB3284) as a potent human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2, an IC50 of 4.7 nM in antagonism of chemotaxis activity, an IC50 of 84 μM in inhibition of the hERG potassium current, a free fraction of 58% in protein binding, high selectivity over other chemokine receptors and G-protein-coupled receptors, and acceptable oral bioavailability in rodents and primates. In human clinical trials, INCB3284 exhibited a pharmacokinetic profile suitable for once-a-day dosing (T 1/2 = 15 h).

Keywords
CCR2; antagonist; chemokine; hERG; oral absorption.
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