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
Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
Pfizer Global Research and Development , Chesterfield Parkway West, St. Louis, Missouri 63017, United States.
ACS Med Chem Lett. 2011 Oct 5;2(12):913-8. doi: 10.1021/ml200199c. eCollection 2011 Dec 8.
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.
我们报告了一种新型（S）-3-氨基吡咯烷系列CCR2拮抗剂的发现。对该新系列进行的构效关系研究，确定了17号化合物（INCB8761/PF-4136309），其具有强效的CCR2拮抗活性、高选择性、较弱的人ether-à-go-go相关基因（hERG）活性以及优异的体外和体内吸收、分布、代谢和排泄（ADMET）特性。INCB8761/PF-4136309已进入人体临床试验阶段。
