4p38

Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with AZD8329

spinqualitylabelsall models 4p38, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4p38 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 21T, CL, NDP Related: 4hfr 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 Inhibition of 11beta-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability. Novel acidic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).,Scott JS, deSchoolmeester J, Kilgour E, Mayers RM, Packer MJ, Hargreaves D, Gerhardt S, Ogg DJ, Rees A, Selmi N, Stocker A, Swales JG, Whittamore PR J Med Chem. 2012 Nov 26;55(22):10136-47. doi: 10.1021/jm301252n. Epub 2012 Nov 7. PMID:23088558 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA