The Lyn kinase activator MLR-1023 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes

• Published in: The Journal of pharmacology and experimental therapeutics 2012-07, Vol.342 (1), p.23-32
• Main Authors: Ochman, Alexander R, Lipinski, Christopher A, Handler, Jeffrey A, Reaume, Andrew G, Saporito, Michael S
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Glucose Tolerance Test - methods; Homeostasis - drug effects; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; Mice; Mice, Inbred ICR; Pyrimidinones - pharmacology; Rats; Receptor, Insulin - metabolism; src-Family Kinases - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.112.192187

MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15-22, 2012). The current studies were designed to define the role of insulin in MLR-1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response. In streptozotocin-treated, insulin-depleted mice, MLR-1023 administration did not affect blood glucose levels. However, MLR-1023 potentiated the glucose-lowering activity of exogenously administered insulin, showing that MLR-1023-mediated blood glucose lowering was insulin-dependent. In a hyperinsulinemic/euglycemic clamp study, orally administered MLR-1023 increased the glucose infusion rate required to sustain blood glucose levels, demonstrating that MLR-1023 increased insulin receptor sensitivity. In chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in HbA1c levels and preservation of pancreatic β-cells. The magnitude of effect was equivalent to that seen with rosiglitazone but with a faster onset of action and without causing weight gain. These studies show that MLR-1023 is an insulin receptor-potentiating agent that produces a rapid-onset and durable blood glucose-lowering activity in diabetic animals.