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1. chinaXiv:201711.02419 [pdf]

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

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)
Subjects: Biology >> Ecology

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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