Core modification of substituted piperidines as Novel inhibitors of HDM2-p53 protein-protein interaction

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• 作者：Weidong Pan^a ; ; Brian R. Lahue^b ; Yao Ma^b ; Latha G. Nair^a ; Gerald W. Shipps Jr.^b ; Yaolin Wang^a ; Ronald Doll^a ; Sté ; phane L. Bogen^a ; ^{Stephane.bogen@merck.com" class="auth_mail}
• 关键词：HDM2 ; p53 ; Protein&ndash ; protein interaction ; Cancer
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 April, 2014
• 年：2014
• 卷：24
• 期：8
• 页码：1983-1986
• 全文大小：697 K

文摘

The discovery of 3,3-disubstituted piperidine 1 as novel p53-HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.