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.
Subject(s)
Adipocytes/drug effects , Amides/pharmacology , Receptor, Insulin/drug effects , 3T3-L1 Cells , Adipocytes/metabolism , Amides/chemical synthesis , Amides/chemistry , Animals , Drug Evaluation, Preclinical , Glucose/pharmacokinetics , Insulin/pharmacology , Mice , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Protease inhibitor (PI) therapy for the treatment of patients infected with human immunodeficiency virus is frequently associated with insulin resistance and diabetic complications. These adverse effects of PI treatment result to a large extent from their inhibition of insulin-stimulated glucose transport. Insulin receptor (IR) activators that enhance the insulin signaling pathway could be effective in treating this resistance. However, there are no agents reported that reverse inhibition of insulin action by PIs. Herein, we describe the effects of TLK19781. This compound is a non-peptide, small molecule, activator of the IR. We now report in cultured cells, made insulin resistant HIV by PI treatment, that TLK19781 both increased the content of insulin-stimulated GLUT4 at the plasma membrane, and enhanced insulin-stimulated glucose transport. In addition, oral administration of TLK19781 with the PI, indinavir improved glucose tolerance in rats made insulin resistant. These results suggest, therefore, that IR activators such as TLK19781 may be useful in treating the insulin resistance associated with PIs.
Subject(s)
HIV Protease Inhibitors/pharmacology , Indinavir/pharmacology , Insulin Resistance , Naphthalenes/pharmacology , Receptor, Insulin/agonists , Sulfanilic Acids/pharmacology , 3T3-L1 Cells , Adipocytes/metabolism , Administration, Oral , Animals , Biological Transport , ErbB Receptors/metabolism , Glucose/metabolism , Glucose Tolerance Test , Glucose Transporter Type 4 , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/adverse effects , In Vitro Techniques , Indinavir/administration & dosage , Indinavir/adverse effects , Mice , Monosaccharide Transport Proteins/metabolism , Muscle Proteins/metabolism , Naphthalenes/administration & dosage , Phosphorylation , Rats , Receptor, Insulin/metabolism , Sulfanilic Acids/administration & dosageABSTRACT
In type 2 diabetes mellitus, impaired insulin signaling leads to hyperglycemia and other metabolic abnormalities. TLK19780, a non-peptide small molecule, is a new member of a novel class of anti-diabetic agents that function as activators of the insulin receptor (IR) beta-subunit tyrosine kinase. In HTC-IR cells, 20 microm TLK19780 enhanced maximal insulin-stimulated IR autophosphorylation 2-fold and increased insulin sensitivity 2-3-fold. In contrast, TLK19780 did not potentiate the action of insulin-like growth factor-1, indicating the selectivity of TLK19780 toward the IR. The predominant effect of TLK19780 was to increase the number of IR that underwent autophosphorylation. Kinetic studies indicated that TLK19780 acted very rapidly, with a maximal effect observed 2 min after addition to insulin-stimulated cells. In 3T3-L1 adipocytes, 5 microm TLK19780 enhanced insulin-stimulated glucose transport, increasing both the sensitivity and maximal responsiveness to insulin. These studies indicate that at low micromolar levels small IR activator molecules can enhance insulin action in various cultured cells and suggest that this effect is mediated by increasing the number of IR that are tyrosine-phosphorylated in response to insulin. These studies suggest that these types of molecules could be developed to treat type 2 diabetes and other clinical conditions associated with insulin resistance.
