ABSTRACT
Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Enzyme Activators/therapeutic use , Glucokinase/metabolism , Hypoglycemic Agents/therapeutic use , Pyrrolidines/therapeutic use , Thiophenes/therapeutic use , Animals , Diabetes Mellitus, Type 2/metabolism , Enzyme Activators/chemistry , Enzyme Activators/pharmacokinetics , Enzyme Activators/pharmacology , Glucose Tolerance Test , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Liver/drug effects , Liver/metabolism , Male , Mice, Inbred C57BL , Pancreas/drug effects , Pancreas/metabolism , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Thiophenes/pharmacologyABSTRACT
In the course of our program for discovery of novel DPP-IV inhibitors, a series of pyrazolo[1,5-a]pyrimidines were found to be novel DPP-IV inhibitors. We identified N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (4a) and described its pharmacological profiles.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Dogs , Humans , Male , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Rats , Rats, Sprague-Dawley , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Focused structure-activity relationships of isoindoline class DPP-IV inhibitors have led to the discovery of 4b as a highly selective, potent inhibitor of DPP-IV. In vivo studies in Wistar/ST rats showed that 4b was converted into the strongly active metabolite 4l in high yield, resulting in good in vivo efficacy for antihyperglycemic activity.
