RT Journal Article SR Electronic T1 HIS-388, a Novel Orally Active and Long-Acting 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, Ameliorates Insulin Sensitivity and Glucose Intolerance in Diet-Induced Obesity and Nongenetic Type 2 Diabetic Murine Models JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 181 OP 189 DO 10.1124/jpet.114.216556 VO 351 IS 1 A1 Seiji Okazaki A1 Takehiro Takahashi A1 Tomokatsu Iwamura A1 Junko Nakaki A1 Yumiko Sekiya A1 Mai Yagi A1 Hiroki Kumagai A1 Mikiya Sato A1 Satoshi Sakami A1 Aiko Nitta A1 Koji Kawai A1 Mie Kainoh YR 2014 UL http://jpet.aspetjournals.org/content/351/1/181.abstract AB 11β-Hydroxysteroid dehydrogenase type 1 (11β-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-2-yl]-3-(pyridin-2-yl) isoxazole-4-carboxamide), a newly synthesized 11β-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 11β-HSD1 inhibitors (carbenoxolone and compound 544 [3-[(1s,3s)-adamantan-1-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine]), indicating that HIS-388 potently and continuously suppresses 11β-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 11β-HSD1 enzyme activity may be an effective approach for the treatment of type 2 diabetes and obesity-associated disease.