4bb5

Free-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11b-Hydroxysteroid Dehydrogenase Type 1 11b-HSD1 Inhibitors

spinqualitylabelsall models 4bb5, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4bb5 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 2.2Å Ligands: HD2, NAP 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 11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) has been a target of intensive research effort across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. In order to demonstrate the value of 11beta-HSD1 in pre-clinical models we required inhibitors with good potency against both human and rodent isoforms. Herein we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described - a data driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD7.4 range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycaemic and bodyweight endpoints in murine disease models, where it demonstrated glucose and bodyweight efficacy at 300 mg/kg/day but only bodyweight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver. Free-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1) Inhibitors.,Goldberg FW, Leach AG, Scott JS, Snelson W, Groombridge S, Donald C, Bennett S, Bodin C, Gutierrez PM, Gyte A J Med Chem. 2012 Nov 16. PMID:23153367 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Hydroxysteroid dehydrogenase 3D structures

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