2. Academic Validation
  3. Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist

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

Affiliation

  • 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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