4c7k | pdb_00004c7k

11b-Hydroxysteroid Dehydrogenase Type I in complex with inhibitor

spinqualitylabelsall models 4c7k, resolution 1.91Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4c7k is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DZL, NAP Related: 4c7j Activity: 11-beta-hydroxysteroid dehydrogenase, with EC number 1.1.1.146 Resources: FirstGlance, OCA, RCSB, PDBsum 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). Publication Abstract from PubMed 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11beta-HSD1 activity alleviates metabolic syndrome. Optimization of brain penetrant 11beta-hydroxysteroid dehydrogenase type I inhibitors and in vivo testing in diet-induced obese mice.,Goldberg FW, Dossetter AG, Scott JS, Robb GR, Boyd S, Groombridge SD, Kemmitt PD, Sjogren T, Gutierrez PM, deSchoolmeester J, Swales JG, Turnbull AV, Wild MJ J Med Chem. 2014 Feb 13;57(3):970-86. doi: 10.1021/jm4016729. Epub 2014 Jan 27. PMID:24422550 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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