5PGU

CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 2-[2-(4-fluorophenyl)-2-adamantyl]-1-(3-methoxyazetidin-1-yl)ethanone

Summary for 5PGU

• Entry DOI: 10.2210/pdb5pgu/pdb
• Group deposition: 11betaHSD1 (G_1002017)
• Descriptor: Corticosteroid 11-beta-dehydrogenase isozyme 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-[2-(4-fluorophenyl)-2-adamantyl]-1-(3-methoxyazetidin-1-yl)ethanone, ... (4 entities in total)
• Functional Keywords: 11b-hsd1, sdr, dehydrogenase, hydroxysteroid, inhibitor, oxidoreductase-oxidoreductase inhibi complex, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Endoplasmic reticulum membrane ; Single-pass type II membrane protein : P28845
• Total number of polymer chains: 4
• Total formula weight: 129788.86

Authors

Sheriff, S. (deposition date: 2017-02-06, release date: 2017-11-01, Last modification date: 2024-03-06)

Primary citation

Ye, X.Y.,Chen, S.Y.,Wu, S.,Yoon, D.S.,Wang, H.,Hong, Z.,O'Connor, S.P.,Li, J.,Li, J.J.,Kennedy, L.J.,Walker, S.J.,Nayeem, A.,Sheriff, S.,Camac, D.M.,Ramamurthy, V.,Morin, P.E.,Zebo, R.,Taylor, J.R.,Morgan, N.N.,Ponticiello, R.P.,Harrity, T.,Apedo, A.,Golla, R.,Seethala, R.,Wang, M.,Harper, T.W.,Sleczka, B.G.,He, B.,Kirby, M.,Leahy, D.K.,Li, J.,Hanson, R.L.,Guo, Z.,Li, Y.X.,DiMarco, J.D.,Scaringe, R.,Maxwell, B.,Moulin, F.,Barrish, J.C.,Gordon, D.A.,Robl, J.A.
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 11 beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitor.
J. Med. Chem., 60:4932-4948, 2017

PubMed Abstract: BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED 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 11β-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.

PubMed: 28537398
DOI: 10.1021/acs.jmedchem.7b00211

Experimental method

X-RAY DIFFRACTION (2.35 Å)