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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.

submitted time 2017-11-17 Hits959Downloads568 Comment 0

2. chinaXiv:201711.02424 [pdf]

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

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)
Subjects: Biology >> Ecology

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.

submitted time 2017-11-17 Hits919Downloads510 Comment 0

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