Title:Design, Synthesis and Evaluation of Novel Derivatives of Orotic Acid Amide as Potent Glucokinase Activators
Volume: 14
Issue: 3
Author(s): Leilei Zhang, Shengquan Hu, Lei Lei, Yuliang Zhang, Lijing Zhang, Hongrui Song, Zhufang Shen and Zhiqiang Feng
Affiliation:
Keywords:
Glucokinase, glucokinase activator, type 2 diabetes, Orotic acid amide derivatives.
Abstract: Background: Glucokinase activators (GKAs) represent a promising opportunity for the treatment
of type 2 diabetes due to the fact that glucokinase (GK) is a key regulator of glucose homeostasis.
Method: Based on structure-based design strategies, a series of novel orotic acid amide derivatives have
been synthesized. Lead optimization led to the discovery of several active compounds via in vitro enzyme
assays. Compared to the positive control compound GKA22, compounds 10j, 11h and 11i exhibited identical
or even higher activity. Furthermore, docking simulation of compound 11i further demonstrated that the
hydrogen atom of amide and the nitrogen atom of pyrimidine both bound to Arg63 via hydrogen bonds.
Results: Hydrogen bond interactions were also observed between the two oxygen atoms of 2-methoxy-1-
methyl-ethoxy moiety and Thr65. Both ends of the molecule were fixed in allosteric pocket of
glucokinase, which was in favour of keeping active conformation.
