title: 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.
abstract: 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.
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan Takehiro_Takahashi@nts.toray.co.jp.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Iwamura
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Nakaki
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sekiya
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Yagi
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kumagai
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Mikiya
authors.initials: M
authors.lastname: Sato
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakami
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Nitta
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
authors.forename: Mie
authors.initials: M
authors.lastname: Kainoh
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000627:therapeutic use; D002229:Carbenoxolone / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D018149:Glucose Intolerance; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009765:Obesity / Q000188:drug therapy*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
chemical_list: C505014:3-(1-adamantyl)-6,7,8,9-tetrahydro-5H-(1,2,4)triazolo(4,3-a)azepine; D001381:Azepines; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007555:Isoxazoles; C000593021:N-(5-hydroxyadamantan-2-yl)-3-(pyridin-2-yl)isoxazole-4-carboxamide; D045162:Thiazolidinediones; D014230:Triazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D002229:Carbenoxolone; D000218:Adamantane; D000077205:Pioglitazone