Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization

• DOI: 10.1016/j.ejmech.2012.03.015
• Publication Date: 2012-03-17T10:15:44Z
• Authors: 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
• Keywords: Metabolic stability; Alogliptin

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.