Discovery of INCB9471, a potent, selective, and orally bioavailable CCR5 antagonist with potent anti-HIV-1 activity

CB Xue, L Chen, G Cao, K Zhang, A Wang…

Index: Xue, Chu-Biao; Chen, Lihua; Cao, Ganfeng; Zhang, Ke; Wang, Anlai; Meloni, David; Glenn, Joseph; Anand, Rajan; Xia, Michael; Kong, Ling; Huang, Taisheng; Feng, Hao; Zheng, Changsheng; Li, Mei; Galya, Laurine; Zhou, Jiacheng; Shin, Niu; Baribaud, Fredric; Solomon, Kim; Scherle, Peggy; Zhao, Bitao; Diamond, Sharon; Emm, Tom; Keller, Douglas; Contel, Nancy; Yeleswaram, Swamy; Vaddi, Kris; Hollis, Gregory; Newton, Robert; Friedman, Steven; Metcalf, Brian ACS Medicinal Chemistry Letters, 2010 , vol. 1, # 9 p. 483 - 487

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Citation Number: 8

Abstract

To identify a CCR5 antagonist as an HIV-1 entry inhibitor, we designed a novel series of indane derivatives based on conformational considerations. Modification on the indane ring led to the discovery of compound 22a (INCB9471) that exhibited high affinity for CCR5, potent anti-HIV-1 activity, high receptor selectivity, excellent oral bioavailability, and a tolerated safety profile. INCB9471 has entered human clinical trials.