Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors

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• 作者：Stéphane L. Bogen ; Weidong Pan ; Craig R. Gibeau ; Brian R. Lahue ; Yao Ma ; Latha G. Nair ; Elise Seigel ; Gerald W. Shipps Jr. ; Yuan Tian ; Yaolin Wang ; Yinghui Lin ; Ming Liu ; Suxing Liu ; Asra Mirza ; Xiaoying Wang ; Philip Lipari ; Cynthia Seidel-Dugan ; Daniel J. Hicklin ; W. Robert Bishop ; Diane Rindgen ; Amin Nomeir ; Winifred Prosise ; Paul Reichert ; Giovanna Scapin ; Corey Strickland ; Ronald J. Doll
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：324-329
• 全文大小：487K
• ISSN：1948-5875

文摘

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23–ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.