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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 351; no. 1; pp. 181 - 189
• Main Authors: Okazaki, Seiji, Takahashi, Takehiro, Iwamura, Tomokatsu, Nakaki, Junko, Sekiya, Yumiko, Yagi, Mai, Kumagai, Hiroki, Sato, Mikiya, Sakami, Satoshi, Nitta, Aiko, Kawai, Koji, Kainoh, Mie
• Format: Journal Article
• Language: English
• Published: United States 01.10.2014
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; Adamantane - analogs & derivatives; Adamantane - pharmacology; Adamantane - therapeutic use; Administration, Oral; Animals; Azepines - therapeutic use; Carbenoxolone - therapeutic use; Diabetes Mellitus, Experimental - drug therapy; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Glucose Intolerance; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin Resistance; Isoxazoles - pharmacology; Isoxazoles - therapeutic use; Male; Mice; Mice, Inbred C57BL; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Obesity - drug therapy; Thiazolidinediones - therapeutic use; Triazoles - therapeutic use
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.114.216556

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.