Rational design and synthesis of 1,5-disubstituted tetrazoles as potent inhibitors of the MDM2-p53 interaction

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• 作者：Ewa Surmiak^a ; Constantinos G. Neochoritis^b ; Bogdan Musielak^a ; Aleksandra Twarda-Clapa^c ; ^d ; Katarzyna Kurpiewska^a ; Grzegorz Dubin^c ; ^d ; Carlos Camacho^e ; Tad A. Holak^a ; ^d ; Alexander Dö ; mling^b ; ^{a.s.s.domling@rug.nl}
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：27 January 2017
• 年：2017
• 卷：126
• 期：Complete
• 页码：384-407
• 全文大小：2072 K
• 卷排序：126

文摘

VS-based discovery of novel 1,5-disubstituted tetrazoles as MDM2 antagonists. >60 compounds were synthesized using a 2-step MCR chemistry. FP-monitored SAR analysis allowed for the fast optimization up to low nM potency. Compound 2.27 inhibited the MDM2/p53 interaction with a Ki of 20 nM. The affinity and the rough binding mode were also confirmed using 2D NMR.