ABSTRACT
In the present investigation, two series of 2,5-disubstituted-3-imidazol-2-yl-pyrrolo[2,3-b]pyridines (2a-l) and thieno[2,3-b]pyridines (3a-l) were designed as analogs of BL 11282 (1). The in vitro glucose dependent insulinotropic activity of all the test compounds was evaluated using RIN5F cell based assay and all the test compounds showed glucose and concentration dependent insulin secretion. The in vivo antidiabetic activities of most potent compounds from each series (2c and 3c) were assessed in C57BL/6J mice. Compounds 2c and 3c showed dose dependent insulin secretion and significant glucose reduction in vivo. In general, compounds 2c and 3c were found to be equipotent at all the three different doses selected and with respect to BL 11282, both the test compounds were found to be more potent, at all the time points.
Subject(s)
Blood Glucose/drug effects , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Animals , Hypoglycemic Agents/chemical synthesis , Insulin/metabolism , Insulin Secretion , Male , Mice , Mice, Inbred C57BL , Pyridines/chemical synthesisABSTRACT
Two series of 3,6,7-trisubstituted-2-(1H-imidazol-2-ylsulfanyl)-quinoxalines 2a-l and 2-(quinoxalin-2-yl)-isothioureas 3a-l were prepared. All the test compounds 2a-l and 3a-l were screened in vitro, in a RIN5F cell-based assay for glucose-dependent insulinotropic activity. A significant concentration and glucose-dependent insulin secretion effect was seen with compounds 2a-l and the insulinotropic activity of compound 2l was found to be identical to that of the standard compound (6,7-dichloro-2-trifluromethyl-3-(5-methyl-1,3,4-thiadiazo-2-ylsulfanyl)-quinoxaline (1)).
Subject(s)
Hypoglycemic Agents/chemical synthesis , Imidazoles/chemical synthesis , Insulin/metabolism , Quinoxalines/chemical synthesis , Sulfones/chemical synthesis , Thiourea/analogs & derivatives , Thiourea/chemical synthesis , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Insulin Secretion , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Quinoxalines/chemistry , Quinoxalines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Thiourea/chemistry , Thiourea/pharmacologyABSTRACT
beta-Carbolines stimulate insulin secretion in a glucose-dependent manner, probably by acting on I(3)-binding site. Knowing the in vitro glucose-dependent insulinotropic potential of beta-carbolines, in this project, three series of substituted-triaza-fluorene-6-carboxylic acids (5a-v, 6a-t, and 7a-t) were designed (analogs of beta-carboline) as a new class of insulinotropic agents. The in vitro glucose-dependent insulinotropic activities of test compounds were evaluated using RIN5F assay. Interestingly, with respect to the control, test compounds showed concentration-dependent insulin release, only in presence of glucose load (16.7 mmol). Some of the test compounds from each series were found to be equipotent to standard compound (Harmane), indicating that the pyridine ring systems of substituted-triaza-fluorenes act as bioisosteres of benzene ring in beta-carbolines.
Subject(s)
Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Insulin/metabolism , Animals , Binding Sites , Carboxylic Acids/chemistry , Carboxylic Acids/classification , Glucose/pharmacology , Insulin Secretion , Molecular Structure , Rabbits , Radioligand Assay , Rats , Receptors, Adrenergic, alpha-2/metabolism , Structure-Activity RelationshipABSTRACT
Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration and therefore cause hypoglycemia in type 2 diabetic patients. Over the last years, a number of aryl-imidazoline derivatives have been identified that stimulate insulin secretion in a glucose-dependent manner. In the present study, we have developed three series of substituted N-(thieno[2,3-b]pyridin-3-yl)-guanidine (2a-l), N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3a-l), and N-(1H-indol-3-yl)-guanidine (4a-l) as new class of antidiabetic agents. In vitro glucose-dependent insulinotropic activity of test compounds 2a-l, 3a-l, and 4a-l was evaluated using RIN5F (Rat Insulinoma cell) based assay. All the test compounds showed concentration-dependent insulin secretion, only in presence of glucose load (16.7mmol). Some of the test compounds (2c, 3c, and 4c) from each series were found to be equipotent to BL 11282 (standard aryl-imidazoline), which indicated that the guanidine group acts as a bioisostere of imidazoline ring system.
