3hfg
Crystal Structure of Human 11-beta-hydroxysteroid-dehydrogenase Bound to an Sulfonyl-piperazine InhibitorCrystal Structure of Human 11-beta-hydroxysteroid-dehydrogenase Bound to an Sulfonyl-piperazine Inhibitor
Structural highlights
Disease[DHI1_HUMAN] Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:604931]. In CRD, activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS). Function[DHI1_HUMAN] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-beta-hydroxycholesterol (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCortisol 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. Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model.,Wan ZK, Chenail E, Xiang J, Li HQ, Ipek M, Bard J, Svenson K, Mansour TS, Xu X, Tian X, Suri V, Hahm S, Xing Y, Johnson CE, Li X, Qadri A, Panza D, Perreault M, Tobin JF, Saiah E J Med Chem. 2009 Sep 10;52(17):5449-61. PMID:19673466[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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