title: A novel highly potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, UI-1499.
abstract: OBJECTIVE
  Elevated levels of glucocorticoid hormones cause glucose intolerance, visceral obesity, insulin resistance, hypertension, and dyslipidemia. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) represents as an attractive therapeutic target for treatment of metabolic syndrome and type 2 diabetes. This study investigated whether 11β-HSD1 inhibition by a novel selective inhibitor, (1S,3R,4S,5S,7S)-4-(1-((2-fluoro-N-methylphenylsulfonamido)-methyl) cyclopropanecarboxamido) adamantane-1-carboxamide (UI-1499) ameliorated metabolic abnormalities in diabetic mice.
  
  
  METHODS
  The in vitro activity of 11β-HSD1 was measured using the homogeneous time resolved fluorescence (HTRF) assay. Differentiated adipocytes were used to evaluate cellular 11β-HSD1 activity. To determine the inhibitory effects on 11β-HSD1 in tissues, we performed ex vivo studies using liver and epididymal fat isolated from C57BL/6J mice. KKAy mice were administered with UI-1499 to evaluate whether this compound ameliorated metabolic abnormalities in vivo in diabetic animals.
  
  
  RESULTS
  UI-1499 had highly potent inhibitory activity in mouse, monkey and human 11β-HSD1, derived from liver microsomes. Oral administration of 45 mg/kg UI-1499 significantly inhibited 11β-HSD1 activity in C57BL/6J mouse liver and epididymal fat tissues. In KKAy mice, oral administration of UI-1499 (10 and 30 mg/kg for 3 weeks) lowered fasting blood glucose and HbA1c levels; these effects were comparable to those of pioglitazone. Further, UI-1499 treatment lowered plasma low-density lipoprotein (LDL) level in KKAy mice.
  
  
  CONCLUSIONS
  These results suggest that the 11β-HSD1 inhibitor, UI-1499, may serve as a novel drug candidate for the treatment of type 2 diabetes and metabolic syndrome.
authors.affiliation: Institute for New Drug Development, Division of Life Sciences, Incheon National University, Incheon 406-772, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Byun
authors.affiliation: R & D Center, Ahn Gook Pharm., Suwon 443-766, Korea.
authors.forename: Young June
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Center for Development and Commercialization of Anti Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, 138-736, Korea.
authors.forename: Ky Youb
authors.initials: KY
authors.lastname: Nam
authors.affiliation: Institute for New Drug Development, Division of Life Sciences, Incheon National University, Incheon 406-772, Korea.
authors.forename: Sung Pyo
authors.initials: SP
authors.lastname: Hong
authors.affiliation: Institute for New Drug Development, Division of Life Sciences, Incheon National University, Incheon 406-772, Korea. Electronic address: skahn@incheon.ac.kr.
authors.forename: Soon Kil
authors.initials: SK
authors.lastname: Ahn
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D016475:3T3 Cells; D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005938:Glucocorticoids / Q000737:chemistry; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: C000595305:4-(1-((2-fluoro-N-methylphenylsulfonamido)methyl)cyclopropanecarboxamido)adamantane-1-carboxamide; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D013449:Sulfonamides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane
keywords: 11β-HSD1 inhibitor; KKAy mice; blood glucose; glucocorticoid; metabolic syndrome; type 2 diabetes