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

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.

SUBMITTER: Xue CB

PROVIDER: S-EPMC4018168 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

Xue Chu-Biao CB Wang Anlai A Han Qi Q Zhang Yingxin Y Cao Ganfeng G Feng Hao H Huang Taisheng T Zheng Changsheng C Xia Michael M Zhang Ke K Kong Lingquan L Glenn Joseph J Anand Rajan R Meloni David D Robinson D J DJ Shao Lixin L Storace Lou L Li Mei M Hughes Robert O RO Devraj Rajesh R Morton Philip A PA Rogier D Joseph DJ Covington Maryanne M Scherle Peggy P Diamond Sharon S Emm Tom T Yeleswaram Swamy S Contel Nancy N Vaddi Kris K Newton Robert R Hollis Greg G Metcalf Brian B

ACS medicinal chemistry letters 20111005 12

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. ...[more]

PMID: 24900280

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