ABSTRACT
A novel series of symmetrical ureas of [(7-amino(2-naphthyl))sulfonyl]phenylamines were designed, synthesized, and tested for their ability to increase glucose transport in mouse 3T3-L1 adipocytes, a surrogate readout for activation of the insulin receptor (IR) tyrosine kinase (IRTK). A structure-activity relationship was established that indicated glucose transport activity was dependent on the presence of two acidic functionalities, two sulfonamide linkages, and a central urea or 2-imidazolidinone core. Compound 30 was identified as a potent and selective IRTK activator. At low concentrations, 30 was able to increase the tyrosine phosphorylation of the IR stimulated by submaximal insulin. At higher concentrations, 30 was able to increase tyrosine the phosphorylation levels of the IR in the absence of insulin. When administered intraperitoneally (ip) and orally (po), 30 improved glucose tolerance in hypoinsulinemic, streptozotocin-treated rats. These data provide pharmacological validation that small molecule IRTK activators represent a potential new class of antidiabetic agents.
Subject(s)
Aniline Compounds/pharmacology , Drug Design , Receptor, Insulin/drug effects , Sulfonamides/pharmacology , Urea/pharmacology , 3T3-L1 Cells , Adipocytes/drug effects , Administration, Oral , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Animals , Binding Sites , Blood Glucose/analysis , Cells, Cultured , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Fibroblasts/drug effects , Glucose Tolerance Test , Injections, Intraperitoneal , Male , Mice , Molecular Structure , Phosphorylation/drug effects , Rats , Rats, Sprague-Dawley , Stereoisomerism , Streptozocin/administration & dosage , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Urea/analogs & derivatives , Urea/chemistryABSTRACT
A novel series of 5-substituted isophthalamides and their structure-activity relationship as insulin receptor sensitizers is discussed.
