pf-04991532 and Diabetes-Mellitus--Type-2

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.

Topics: Allosteric Regulation; Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Enzyme Activators; Glucokinase; Hepatocytes; Humans; Hypoglycemic Agents; Imidazoles; Injections, Intravenous; Niacin; Rats; Tissue Distribution

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

Topics: Allosteric Site; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dogs; Enzyme Activators; Glucokinase; Haplorhini; Hepatocytes; Humans; Hypoglycemic Agents; Imidazoles; In Vitro Techniques; Insulin-Secreting Cells; Male; Models, Molecular; Nicotinic Acids; Organic Anion Transporters; Protein Binding; Rats; Rats, Sprague-Dawley; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution