分类： 物理学 >> 普通物理:统计和量子力学,量子信息等 提交时间： 2017-11-17
Shaogao Zeng
Hui Xiea
Lili Zeng
Xin Lu
Xin Zhao
Guicheng Zhang
Zhengchao Tu
Hongjiang Xu
Ling Yang
Xiquan Zhang
Wenhui Hu
摘要： A new chemical class of potent DPP-IV inhibitors has been structurally derived from our recently disclosed pyrrolopyrimidine scaffold by replacing cyanobenzyl with butynyl group. Systematic variations and structure-activity relationship studies have been conducted on the starting hit 51 (IC50= 0.46 μM). Consequently, compound 78 (IC50= 1.55 nM) was identified to be a potent, selective, and orally available lead, worth further evaluations and optimizations.
分类： 物理学 >> 普通物理:统计和量子力学,量子信息等 提交时间： 2017-11-17
Hui Xie
Lili Zeng
Shaogao Zeng
Xin Lu
Xin Zhao
Guicheng ZhangZhengchao Tu
Hongjiang Xu
Ling Yang
Xiquan Zhang
Wenhui Hua
摘要： The structural superposition of DPP-IV complex with Alogliptin and Linagliptin displayed a similar binding mode. The butynyl of Linagliptin and cyanobenzyl of Alogliptin occupy the S1 pocket which therefore could be mutually switched. Thus a pharmacophore hybridization of Alogliptin was initiated and led to a novel DPP-IV inhibitor 61. Though it did not exhibit desired activity (IC50= 0.2 礛), the butynyl compound acts as a lead compound triggered a following structural optimization. A novel series of potent DPP-IV inhibitors represented by compound 77 (IC50= 0.36 nM) were obtained with a robust pharmacokinetic profile and better in vitro and in vivo efficacy than Alogliptin.
分类： 生物学 >> 生态学 提交时间： 2017-11-17
Hui Xie
Saogao Zeng
Lili Zeng
Xiaobing Lan
Guicheng Zhang
Li Liu
Xin Lu
Na Chen
Zhiyuan Li
Zengzhao Tu
Hongjiang Xu
Ling Yang
Xiquan Zhang
Wenhui Hu
摘要： Followed pharmacological evaluation exposed an extensive hepatic first pass effect within our recently disclosed DPP-IV inhibitors bearing thienopyrimidine scaffold. Through scaffold replacement with pyrrolopyrimidine, compound 1a had substantially improved the metabolic stability (from 6.6% to 65.07%), yet with severely poor absorptive property. Further modification by incorporation with varied substituents and structure conversion yielded both permeable and metabolic stable compounds. The whole pharmacokinetic- property based optimization had succeeded in balancing overall properties and resulted in the compound 1j, that with excellent efficacy to be a potential anti-diabetic candidate.
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