5pgw | pdb_00005pgw
CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 2-[(1R,3S,5R,7S)-2-[4-(4-FLUOROPHENYL)PHENYL]-6-HYDROXYADAMANTAN-2-YL]-1-(3- HYDROXYAZETIDIN-1-YL)ETHAN-1-ONE
Structural highlights
DiseaseDHI1_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). FunctionDHI1_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 PubMedBMS-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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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