l-783281 and Diabetes-Mellitus

Topics: Administration, Oral; Diabetes Mellitus; Humans; Hypoglycemic Agents; Indoles; Insulin; Receptor, Insulin

Orally available anti-diabetic candidates, reported by Merck researchers, are reviewed. The lead, asterriquinone B1(1a), was discovered in a fungal extract by screening with the cell line CHO.IR. An analog, 2,5-dihydroxy-3-(1-methylindol-3-yl)-6-phenyl-1,4-benzoquinone(2h), was selected by studying structure-activity relationships with various in vitro and in vivo tests. Analog 2h exhibited selective tyrosin kinase activity to an insulin receptor and a glucose-lowering effect by testing on diabetic rodent models. However, on the basis of the results of in vivo tests on streptozotocin-induced and on normal lean mice, the activity of 2h was attributed to a sensitizing effect on insulin together with an insulin mimetic effect in part. These studies shed light on the search for new anti-diabetic agents by targeting insulin receptors.

Topics: Administration, Oral; Animals; Benzoquinones; Diabetes Mellitus; Humans; Hypoglycemic Agents; Indolequinones; Indoles; Insulin Resistance; Structure-Activity Relationship

Insulin elicits diverse biological responses in many tissues and cell types by binding to its specific receptor. The insulin receptor (IR) is a tetramer consisting of two extracellular alpha subunits and two membrane-spanning beta subunits. The binding of insulin to the receptor causes conformational changes that lead to autophosphorylation and activation of the tyrosine kinase intrinsic to the beta subunits. Insulin receptor transphosphorylates several immediate substrates, resulting in modulation of a cascade of downstream signal transduction molecules. In order to discover small molecules that activate the human insulin receptor tyrosine kinase (IRTK), a cell-based assay was established and utilized to screen a collection of synthetic chemicals and natural product extracts. This effort led to the identification of a nonpeptidyl, small molecule, insulin-mimetic compound (demethylasterriquinone B-1, DMAQ-B1) that was isolated from a mixture of metabolites produced by a tropical endophytic fungus, Pseudomassaria sp. This compound induced human IRTK activation and increased tyrosine phosphorylation of IR beta subunit. It mediated insulin-like effects, including insulin receptor substrate-1 (IRS-1) phosphorylation and activation of phosphotidylinositide 3-kinase and Akt kinase. DMAQ-B1 also exhibited an insulin-like effect on glucose uptake in adipocytes and skeletal muscle tissue. Furthermore, the compound was relatively selective for IR vs. insulin-like growth factor-I (IGF-I) receptor and other homologous receptor tyrosine kinases. In addition, it activated partially purified native IR or recombinant IR kinase, demonstrating the direct interaction of the small molecule with the IR. Oral administration of DMAQ-B1 resulted in significant glucose lowering in two mouse models of diabetes. Thus, DMAQ-B1 represents the first orally active insulin-mimetic agent. Pharmaceutical intervention aimed at augmenting IR function ultimately may prove beneficial as a novel therapeutic option in patients with diabetes.

Topics: Adipocytes; Animals; Arabidopsis Proteins; Ascomycota; CHO Cells; Chromatography, High Pressure Liquid; Cricetinae; Diabetes Mellitus; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Glucose; Humans; Indoles; Insulin; Kinetics; Mice; Models, Chemical; Muscle, Skeletal; Phosphatidylinositol 3-Kinases; Phosphorylation; Plant Proteins; Potassium Channels; Protein Binding; Protein Conformation; Protein-Tyrosine Kinases; Quinones; Receptor, IGF Type 1; Receptor, Insulin; Recombinant Proteins; Signal Transduction; Substrate Specificity