Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model.
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.
Wan
Zhao-Kui
ZK
Chemical Sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA. zwan@wyeth.com
Chenail
Eva
E
Xiang
Jason
J
Li
Huan-Qiu
HQ
Ipek
Manus
M
Bard
Joel
J
Svenson
Kristine
K
Mansour
Tarek S
TS
Xu
Xin
X
Tian
Xianbin
X
Suri
Vipin
V
Hahm
Seung
S
Xing
Yuzhe
Y
Johnson
Christian E
CE
Li
Xiangping
X
Qadri
Ariful
A
Panza
Darrell
D
Perreault
Mylene
M
Tobin
James F
JF
Saiah
Eddine
E
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
D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1