Discovery of potent dipeptidyl peptidase IV inhibitors through pharmacophore hybridization and hit-to-lead optimization

分类： 生物学 >> 生态学 提交时间： 2017-11-17

Zeng, SG (Zeng, Shaogao) Xie, H (Xie, Hui) Zeng, LL (Zeng, Li-li) Lu, X (Lu, Xin) Zhao, X (Zhao, Xin) Zhang, GC (Zhang, Gui-cheng) Tu, ZC (Tu, Zheng-chao) Xu, HJ (Xu, Hong-jiang) Yang, L (Yang, Ling) Zhang, XQ (Zhang, Xi-quan) Hu, WH (Hu, Wenhui)

摘要： A novel dipeptidyl peptidase IV inhibitor hit (5, IC50 = 0.86 mu M) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 180 (IC50 = 1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity: 41% vs 82.9%; T-1/2: 2 h vs 4.9 h). (C) 2013 Elsevier Ltd. All rights reserved.

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