MLR-1023 [tolimidone; CP-26154; 5-(3-methylphenoxy)-2(1H)-pyrimidinone] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test. Ochman et al. attempt 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 with the activities of selected existing diabetes therapeutic agents. 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 chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in hemoglobin A1c levels, and preservation of pancreatic β-cells. The magnitude of effect was equivalent to that of rosiglitazone but with a faster onset of action and without causing weight gain. Results from these studies demonstrate that MLR-1023 is a unique insulin-sensitizing agent that produces rapid-onset and durable blood glucose-lowering activity in diabetic animals and is clearly distinct from activators of peroxisome proliferator-activated receptors.
See article at J Pharmacol Exp Ther 2012, 342:23–32.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics