Identification and structureeactivity relationship exploration of uracil-based benzoic acid and ester derivatives as novel dipeptidyl Peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus
Identification and structureeactivity relationship exploration of uracil-based benzoic acid and ester derivatives as novel dipeptidyl Peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus
复制标题
基于尿嘧啶的苯甲酸和酯衍生物作为新型二肽基肽酶 4 抑制剂用于治疗 2 型糖尿病的鉴定和构效关系探索。
DOI：
10.1016/j.ejmech.2021.113765
复制
发表时间：
2021-08-13
影响因子：
6.7
通讯作者：
Xu, Yanjun
中科院分区：
文献类型：
--
作者：
Li, Qing;Deng, Xiaoyan;Xu, Yanjun
Our previously reported carboxyl-containing DPP-4 inhibitors were highly potent but were poorly bioavailable. Esters of the carboxyl analogs exhibited a significant DPP-4 potency loss albeit with enhanced oral absorption. Herein, we described identification and structureeactivity relationship (SAR) exploration of a novel series of benzoic acid and ester derivatives as low single-digit nanomolar DPP-4 inhibitors. Importantly, the esters displayed comparable activities to the acids counterparts. Molecular simulation revealed that ester adopts a similar binding mode to acid. Moreover, the selected esters and acids demonstrated high selectivity and low cytotoxicity, as well as good metabolic stability. And more importantly, the esters possessed excellent pharmacokinetic profiles for oral administration. The best compound ester 19b demonstrated long DPP-4 inhibition in vivo, and robustly improved the glucose tolerance in normal and db/ db mice while ensuring glucose-lowering potency in chronic treatment. Our results supported that the compound 19b can be served as a potential candidate for the treatment of type 2 diabetes. (C) 2021 Elsevier Masson SAS. All rights reserved.
