4k1l

4,4-Dioxo-5,6-dihydro-[1,4,3]oxathiazines, a novel class of 11 beta-HSD1 inhibitors for the treatment of diabetes

spinqualitylabelsall models 4k1l, resolution 1.96Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4k1l is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.96Å Ligands: NDP, SFF 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 Racemic cis-1,1-dioxo-5,6-dihydro-[4,1,2]oxathiazine derivative 4a was isolated as an impurity in a sample of a hit from a HTS campaign on 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). After separation by chiral chromatography the 4a-S, 8a-R enantiomer of compound 4a was identified as the true, potent enzyme inhibitor. The cocrystal structure of 4a with human and murine 11ss-HSD1 revealed the unique binding mode of the oxathiazine series. SAR elucidation and optimization in regard to metabolic stability led to monocyclic tetramethyloxathiazines as exemplified by compound 21g. 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11ss-HSD1 inhibitors for the treatment of diabetes.,Bohme T, Engel CK, Farjot G, Gussregen S, Haack T, Tschank G, Ritter K Bioorg Med Chem Lett. 2013 Aug 15;23(16):4685-91. doi:, 10.1016/j.bmcl.2013.05.102. Epub 2013 Jun 11. PMID:23845218 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Hydroxysteroid dehydrogenase 3D structures

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