ABSTRACT
Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase ß-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.
Subject(s)
Benzeneacetamides/chemical synthesis , Diabetes Mellitus, Type 2/drug therapy , Enzyme Activators/chemical synthesis , Glucokinase/metabolism , Hypoglycemic Agents/chemical synthesis , Animals , Benzeneacetamides/pharmacokinetics , Benzeneacetamides/pharmacology , Dogs , Enzyme Activators/pharmacokinetics , Enzyme Activators/pharmacology , Female , Glucose/metabolism , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Lipidoses/metabolism , Liver/metabolism , Macaca fascicularis , Male , Mice , Mice, Inbred C57BL , Postprandial Period , Rabbits , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucokinase/drug effects , Hypoglycemic Agents/chemistry , Sulfones/pharmacology , Thiazoles/pharmacology , Animals , Blood Glucose , Cell Line , Cytotoxins , Dose-Response Relationship, Drug , Drug Discovery , Humans , Insulin , Male , Mice , Pharmacokinetics , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/toxicity , Thiazoles/chemistry , Thiazoles/toxicityABSTRACT
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
Subject(s)
Indans/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Crystallography, X-Ray , Humans , Indans/chemistry , Indans/pharmacokinetics , Kinetics , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/chemistry , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.
