Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally Bioavailable CCR2 Antagonist

  • ACS Med Chem Lett. 2011 Oct 5;2(12):913-8. doi: 10.1021/ml200199c.
Chu-Biao Xue  1 ,  Anlai Wang  1 ,  Qi Han  1 ,  Yingxin Zhang  1 ,  Ganfeng Cao  1 ,  Hao Feng  1 ,  Taisheng Huang  1 ,  Changsheng Zheng  1 ,  Michael Xia  1 ,  Ke Zhang  1 ,  Lingquan Kong  1 ,  Joseph Glenn  1 ,  Rajan Anand  1 ,  David Meloni  1 ,  D J Robinson  1 ,  Lixin Shao  1 ,  Lou Storace  1 ,  Mei Li  1 ,  Robert O Hughes  2 ,  Rajesh Devraj  2 ,  Philip A Morton  2 ,  D Joseph Rogier  2 ,  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 ,  Brian Metcalf  1
Affiliations
  • 1. Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
  • 2. Pfizer Global Research and Development , Chesterfield Parkway West, St. Louis, Missouri 63017, United States.
PMID: 24900280 DOI: 10.1021/ml200199c
Abstract

We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in vivo ADMET profile. INCB8761/PF-4136309 has entered human clinical trials.

Keywords
CCR2; antagonist; chemokine; hERG.
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