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.
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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