Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors

  • ACS Med Chem Lett. 2015 Apr 8;6(5):602-6. doi: 10.1021/acsmedchemlett.5b00074.
Tao Jiang  1 ,  Yuren Zhou  1 ,  Zhuxi Chen  1 ,  Peng Sun  1 ,  Jianming Zhu  1 ,  Qiang Zhang  1 ,  Zhen Wang  1 ,  Qiang Shao  1 ,  Xiangrui Jiang  1 ,  Bo Li  1 ,  Kaixian Chen  1 ,  Hualiang Jiang  1 ,  Heyao Wang  1 ,  Weiliang Zhu  1 ,  Jingshan Shen  1
Affiliations
  • 1. Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
PMID: 26005541 DOI: 10.1021/acsmedchemlett.5b00074
Abstract

Dipeptidyl peptidase-4 (DPP-4) inhibitors are accepted as a favorable class of agents for the treatment of type 2 diabetes. Herein, a series of fused β-homophenylalanine derivatives as novel DPP-4 inhibitors were designed, synthesized, and evaluated for their inhibitory activities against DPP-4. Most of them displayed excellent DPP-4 inhibitory activities and good selectivity. Among them, 9aa, 18a, and 18m also showed good efficacy in an oral glucose tolerance test (OGTT) in ICR mice. Moreover, when dosed 8 h prior to glucose challenge, 18m showed significantly greater potency than sitagliptin. It thus provides potential candidates for the further development into potent drugs targeting DPP-4.

Keywords
DPP-4 inhibitor; Diabetes; sitagliptin; β-homophenylalanine derivatives.