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

Chu-Biao Xue; Anlai Wang; Qi Han; Yingxin Zhang; Ganfeng Cao; Hao Feng; Taisheng Huang; Changsheng Zheng; Michael Xia; Ke Zhang; Lingquan Kong; Joseph Glenn; Rajan Anand; David Meloni; D J Robinson; Lixin Shao; Lou Storace; Mei Li; Robert O Hughes; Rajesh Devraj; Philip A Morton; D Joseph Rogier; Maryanne Covington; Peggy Scherle; Sharon Diamond; Tom Emm; Swamy Yeleswaram; Nancy Contel; Kris Vaddi; Robert Newton; Greg Hollis; Brian Metcalf

doi:10.1021/ml200199c

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. eCollection 2011 Dec 8.

Authors

Chu-Biao Xue¹, Anlai Wang¹, Qi Han¹, Yingxin Zhang¹, Ganfeng Cao¹, Hao Feng¹, Taisheng Huang¹, Changsheng Zheng¹, Michael Xia¹, Ke Zhang¹, Lingquan Kong¹, Joseph Glenn¹, Rajan Anand¹, David Meloni¹, D J Robinson¹, Lixin Shao¹, Lou Storace¹, Mei Li¹, Robert O Hughes², Rajesh Devraj², Philip A Morton², D Joseph Rogier², Maryanne Covington¹, Peggy Scherle¹, Sharon Diamond¹, Tom Emm¹, Swamy Yeleswaram¹, Nancy Contel¹, Kris Vaddi¹, Robert Newton¹, Greg Hollis¹, Brian Metcalf¹

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.

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.