4hfr

Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with an orally bioavailable acidic inhibitor AZD4017.

spinqualitylabelsall models 4hfr, resolution 2.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4hfr is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 14M, NAP Gene: HSD11B1, HSD11, HSD11L (HUMAN) Activity: 11-beta-hydroxysteroid dehydrogenase, with EC number 1.1.1.146 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 Inhibition of 11beta-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11beta-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development. Discovery of a potent, selective, and orally bioavailable acidic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acet ic acid (AZD4017).,Scott JS, Bowker SS, Deschoolmeester J, Gerhardt S, Hargreaves D, Kilgour E, Lloyd A, Mayers RM, McCoull W, Newcombe NJ, Ogg D, Packer MJ, Rees A, Revill J, Schofield P, Selmi N, Swales JG, Whittamore PR J Med Chem. 2012 Jun 28;55(12):5951-64. Epub 2012 Jun 19. PMID:22691057 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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