HIS-388, a Novel Orally Active and Long-Acting 11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, Ameliorates Insulin Sensitivity and Glucose Intolerance in Diet-Induced Obesity and Nongenetic Type 2 Diabetic Murine Models

11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is considered a potential therapeutic target in the treatment of type 2 diabetes mellitus. In this study, we investigated the pharmacological properties of HIS-388 (N-[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2yl]-3-(pyridin-2-yl) isoxazole-4-carboxamide), a newly synthesized 11b-HSD1 inhibitor, using several mouse models. In cortisone pellet–implanted mice in which hypercortisolism and hyperinsulinemia occur, single administration of HIS-388 exhibited potent and prolonged suppression of plasma cortisol and lowered plasma insulin levels. These effects were more potent than those achieved using the same dose of other 11b-HSD1 inhibitors (carbenoxolone and compound 544 [3-[(1s,3s)-adamantan-1-yl]-6,7,8,9-tetrahydro5H-[1,2,4]triazolo[4,3-a]azepine]), indicating that HIS-388 potently and continuously suppresses 11b-HSD1 enzyme activity in vivo. In diet-induced obese mice, HIS-388 significantly decreased fasting blood glucose, plasma insulin concentration, and homeostasis model assessment–insulin resistance score, and ameliorated insulin sensitivity. In addition, HIS-388 significantly reduced body weight and suppressed the elevation of blood glucose during the pyruvate tolerance test. In nongenetic type 2 diabetic mice with disease induced by a high-fat diet and low-dose streptozotocin, HIS-388 also significantly decreased postprandial blood glucose and plasma insulin levels and improved glucose intolerance. The effects of HIS-388 on glucose metabolism were indistinguishable from those of an insulin sensitizer, pioglitazone. Our results suggest that HIS-388 is a potent agent against type 2 diabetes. Moreover, amelioration of diabetic symptoms by HIS-388 was at least in part attributable to an antiobesity effect or improvement of hepatic insulin resistance. Therefore, potent and long-lasting inhibition of 11b-HSD1 enzyme activity may be an effective approach for the treatment of type 2 diabetes and obesityassociated disease.