Li Chen, Yongqiang Shan, Xiaowei Jin
Jun 1, 2019
Citations
0
Influential Citations
3
Citations
Quality indicators
Journal
Diabetes
Abstract
Over the last two decades, many glucokinase activators (GKAs) advanced into clinical studies but failed to achieve proof of concept as antidiabetics until the most recent success of Dorzagliatin (a.k.a. HMS5552). Desirable pharmacokinetic (PK) and pharmacodynamic (PD) properties of Dorzagliatin in human subjects offer clear advantage over many GKAs previously in clinical trial. Dorzagliatin benefits also from its desirable enzyme kinetic properties that improve GK’s glucose sensor function and restore glucose homeostasis. Herein we report our recent results on 5 GKAs which all advanced into Phase II clinical studies, some suffered hypoglycemia and others lacked durable efficacy in T2D patients. We evaluated key parameters in GK activation that include α, β and nH in nonessential-mixed type enzyme kinetics equation, as well as the changes under various glucose and drug concentrations. Here β represents the change in Vmax and associates with the ability of GKA to restore GK’s glucose sensor function. Partial GKAs such as AZD1656 and PF-04937319 showed β Disclosure L. Chen: Employee; Self; Hua Medicine. Y. Shan: None. X. Jin: None. X. Lv: None.