MK-0941

Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.

A review.Glucokinase activators are newly drug class proposed for diabetes treatment.This systematic review aimed to assess the efficacy and safety of GKAs in type 2 diabetes mellitus compared to placebo for their readiness in clin. practice and future development.Randomized-controlled trials reported in English were assessed in terms of study quality, placebo-corrected efficacy on glycemic control, and list of safety issues.Thirteen studies were included comprising of eight candidates for GKAs namely AMG 151 (ARRY-403), AZD1656, dorzagliatin, MK-0941, PF-04937319, PF-04991532, RO4389620 (piragliatin), and TTP399.Of the promising GKAs, efficacy on glycemic control was demonstrated on HbA1c reduction more than fasting plasma glucose and 2-h post prandial glucose.Direct GKAs revealed great potency, but more selective GKAs offered certain moderation.This was due to some raised concerns such as hypoglycemia, triglyceride alteration, and adverse events leading to discontinuation.Regardless of limited data, some factors might influence the effects of GKAs in T2DM, for example, structure-mol. aspect, varied trial settings, and diversity in participants′ background.These findings shed light in diabetes management.However, mechanisms towards the unmet benefits of GKAs in T2DM should be tackled.