5PGV

CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 1-(3-HYDROXYAZETIDIN-1-YL)-2-[(2S,5R)-2-(4-FLUOROPHENYL)-5-METHOXYADAMANTAN-2-YL]ETHAN-1-ONE

5PGV の概要

• エントリーDOI: 10.2210/pdb5pgv/pdb
• Group deposition: 11betaHSD1 (G_1002017)
• 分子名称: Corticosteroid 11-beta-dehydrogenase isozyme 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1-(3-HYDROXYAZETIDIN-1-YL)-2-[(2S,5R)-2-(4-FLUOROPHENYL)-5-METHOXYADAMANTAN-2-YL]ETHAN-1-ONE, ... (4 entities in total)
• 機能のキーワード: 11b-hsd1, sdr, dehydrogenase, hydroxysteroid, inhibitor, oxidoreductase-oxidoreductase inhibi complex, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endoplasmic reticulum membrane ; Single-pass type II membrane protein : P28845
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 129852.86

構造登録者

Sheriff, S. (登録日: 2017-02-06, 公開日: 2017-11-01, 最終更新日: 2026-02-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.35 Å)