PF-04651887

PF-04651887 is a small molecule glucokinase activator (GKA) that was under development by Pfizer for the treatment of type 2 diabetes. Glucokinase acts as a glucose sensor in pancreatic beta cells and the liver, and its activation enhances insulin secretion and hepatic glucose uptake. However, preclinical toxicity studies of PF-04651887 and related GKAs revealed significant safety concerns, including severe hypoglycemia, brain neuronal necrosis, peripheral neuropathy, and arteriopathy (specifically of cardiac vessels) in animal models. These adverse effects, particularly the vascular lesions, were hypothesized to be secondary to prolonged hypoglycemia and subsequent catecholamine release or endothelial dysfunction. Due to these safety findings, development of PF-04651887 was discontinued.