Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization
作者:Hui Xie、Lili Zeng、Shaogao Zeng、Xin Lu、Guicheng Zhang、Xin Zhao、Na Cheng、Zhengchao Tu、Zhiyuan Li、Hongjiang Xu、Ling Yang、Xiquan Zhang、Min Huang、Junling Zhao、Wenhui Hu
DOI:10.1016/j.ejmech.2012.03.015
日期:2012.6
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.