title: Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model.
abstract: Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.
authors: Chemical Sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA. zwan@wyeth.com
authors: Zhao-Kui
authors: ZK
authors: Wan
authors: Eva
authors: E
authors: Chenail
authors: Jason
authors: J
authors: Xiang
authors: Huan-Qiu
authors: HQ
authors: Li
authors: Manus
authors: M
authors: Ipek
authors: Joel
authors: J
authors: Bard
authors: Kristine
authors: K
authors: Svenson
authors: Tarek S
authors: TS
authors: Mansour
authors: Xin
authors: X
authors: Xu
authors: Xianbin
authors: X
authors: Tian
authors: Vipin
authors: V
authors: Suri
authors: Seung
authors: S
authors: Hahm
authors: Yuzhe
authors: Y
authors: Xing
authors: Christian E
authors: CE
authors: Johnson
authors: Xiangping
authors: X
authors: Li
authors: Ariful
authors: A
authors: Qadri
authors: Darrell
authors: D
authors: Panza
authors: Mylene
authors: M
authors: Perreault
authors: James F
authors: JF
authors: Tobin
authors: Eddine
authors: E
authors: Saiah
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008968:Molecular Conformation; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1