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<1 and were less effective in blood glucose control. In contrast, Piragliatin and Dorzagliatin showed β value of 1.74 and 1.40 respectively, both demonstrated sustained and significant HbA1c reduction. Changes of nH result in alteration of GK’s glucose dependence and the degree of changes in nH is dependent on GKA concentration. Significant changes in nH by MK-0941 (nH = 1.21 at 10 μM GKA vs. 1.86 without GKA) correlate with its hypoglycemia risk in T2D subjects as shown in clinical trials. Our results strongly indicate that % change in nH at 10 uM GKA shall not go beyond 20% compared with drug free state. Lastly, α values for 5 GKAs all seem to fall in the range of 0.005 to 0.016, thus not appear to correlate with the behavior in clinical trials. The current study provides valuable insight to elucidate some key properties contributing to successful development of a GKA that repairs the glucose sensor function and remodels homeostasis.


L. Chen: Employee; Self; Hua Medicine. Y. Shan: None. X. Jin: None. X. Lv: None.

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