5pgz

CRYSTAL STRUCTURE OF MURINE 11BETA- HYDROXYSTEROIDDEHYDROGENASE COMPLEXED WITH 2-[(5R,7S)-6-HYDROXY-2-PHENYLADAMANTAN-2-YL]-1-(3-HYDROXYAZETIDIN-1-YL)ETHAN-1-ONE (BMS-816336)

spinqualitylabelsall models 5pgz, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5pgz is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.9Å Ligands: 8KG, NAP, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DHI1_MOUSE Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Publication Abstract from PubMed BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11beta-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control. Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitor.,Ye XY, Chen SY, Wu S, Yoon DS, Wang H, Hong Z, O'Connor SP, Li J, Li JJ, Kennedy LJ, Walker SJ, Nayeem A, Sheriff S, Camac DM, Ramamurthy V, Morin PE, Zebo R, Taylor JR, Morgan NN, Ponticiello RP, Harrity T, Apedo A, Golla R, Seethala R, Wang M, Harper TW, Sleczka BG, He B, Kirby M, Leahy DK, Li J, Hanson RL, Guo Z, Li YX, DiMarco JD, Scaringe R, Maxwell B, Moulin F, Barrish JC, Gordon DA, Robl JA J Med Chem. 2017 Jun 22;60(12):4932-4948. doi: 10.1021/acs.jmedchem.7b00211. Epub, 2017 Jun 5. PMID:28537398 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Hydroxysteroid dehydrogenase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA