2. Academic Validation
  3. Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model

Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model

  • J Med Chem. 2009 Sep 10;52(17):5449-61. doi: 10.1021/jm900639u.
Zhao-Kui Wan 1,  Eva Chenail,  Jason Xiang,  Huan-Qiu Li,  Manus Ipek,  Joel Bard,  Kristine Svenson,  Tarek S Mansour,  Xin Xu,  Xianbin Tian,  Vipin Suri,  Seung Hahm,  Yuzhe Xing,  Christian E Johnson,  Xiangping Li,  Ariful Qadri,  Darrell Panza,  Mylene Perreault,  James F Tobin,  Eddine Saiah
Affiliations

Affiliation

  • 1 Chemical Sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA. zwan@wyeth.com
PMID: 19673466 DOI: 10.1021/jm900639u
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.

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