Highly potent dipeptidyl peptidase IV inhibitors derived from Alogliptin through pharmacophore hybridization and lead optimization

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• 作者：Hui Xie ; Lili Zeng ; Shaogao Zeng ; Xin Lu ; Xin Zhao ; Guicheng Zhang ; Zhengchao Tu ; Hongjiang Xu ; Ling Yang ; Xiquan Zhang ; Shanchun Wang ; Wenhui Hu
• 关键词：DPP-IV inhibitor ; Type 2 diabetes ; Superposition ; Pharmacophore hybridization ; In vivo
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：68
• 期：Complete
• 页码：312-320
• 全文大小：1310 K

文摘

The superposition of the DPP-IV complex revealed that the butynyl group of Linagliptin can be freely switched with the cyanobenzyl group of Alogliptin. Thus, a pharmacophore hybridization of Alogliptin was initiated and led to a novel DPP-IV inhibitor, 11a. Although it did not exhibit the desired activity (IC₅₀?=?0.2?¦ÌM), compound 11a acts as a lead compound, which triggered a resulting structural optimization and the formation of compound 11m. A novel series of potent DPP-IV inhibitors represented by compound 11m (IC₅₀?=?0.4?nM) was ultimately obtained with a robust pharmacokinetic profile and superior in?vitro and in?vivo efficacy compared to Alogliptin.