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

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

doi:10.1021/ml200199c.s001

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

journal contribution

posted on 2011-12-08, 00:00 authored by 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

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.