Discovery of novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on a pharmacokinetic property-driven optimization

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.

同行评议状态:待评议

 点击量 2420  下载量 1340  评论