Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization

分类： 生物学 >> 生态学 提交时间： 2017-11-17

Xie, H(Xie, Hui) Zeng, LL(Zeng, Lili) Zeng, SG(Zeng, Shaogao) Lu, X (Lu, Xin) Zhang, GC (Zhang, Guicheng) Zhao, X (Zhao, Xin) Cheng, N (Cheng, Na) Tu, ZC (Tu, Zhengchao) Li, ZY (Li, Zhiyuan) Xu, HJ (Xu, Hongjiang) Yang, L (Yang, Ling) Zhang, XQ (Zhang, Xiquan) Huang, M (Huang, Min) Zhao, JL (Zhao, Junling) Hu, WH (Hu, Wenhui)

摘要： We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development. (C) 2012 Elsevier Masson SAS. All rights reserved.

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