新型3,3-二取代哌啶类化合物作为口服生物可利用、强效且有效的HDM2-p53抑制剂的发现。
Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.
作者信息
Bogen Stéphane L, Pan Weidong, Gibeau Craig R, Lahue Brian R, Ma Yao, Nair Latha G, Seigel Elise, Shipps Gerald W, Tian Yuan, Wang Yaolin, Lin Yinghui, Liu Ming, Liu Suxing, Mirza Asra, Wang Xiaoying, Lipari Philip, Seidel-Dugan Cynthia, Hicklin Daniel J, Bishop W Robert, Rindgen Diane, Nomeir Amin, Prosise Winifred, Reichert Paul, Scapin Giovanna, Strickland Corey, Doll Ronald J
机构信息
Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States.
出版信息
ACS Med Chem Lett. 2016 Jan 20;7(3):324-9. doi: 10.1021/acsmedchemlett.5b00472. eCollection 2016 Mar 10.
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.
以21为代表的新型取代哌啶子系列作为p53-HDM2抑制剂已从初始先导化合物1开发而来。研究聚焦于优化关键的HDM2 Trp23-配体相互作用，从而确定2-(三氟甲基)噻吩为优选部分。对Leu26口袋的进一步研究产生了高效、新型的HDM2-p53相互作用取代哌啶抑制剂，这些抑制剂在几种小鼠人癌异种移植模型中显示出肿瘤消退。描述了HDM2与抑制剂3、10和21形成的复合物的结构。
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