5HU1

BACE1 in complex with (R)-N-(3-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-4-fluorophenyl)-5-fluoropicolinamide

5HU1 の概要

• エントリーDOI: 10.2210/pdb5hu1/pdb
• 関連するPDBエントリー: 5HTZ 5HU0
• 分子名称: Beta-secretase 1, N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide (3 entities in total)
• 機能のキーワード: alzheimer's, aspartyl protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P56817
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 92777.98

構造登録者

Orth, P. (登録日: 2016-01-27, 公開日: 2016-11-09, 最終更新日: 2024-11-20)

主引用文献

Scott, J.D.,Li, S.W.,Brunskill, A.P.,Chen, X.,Cox, K.,Cumming, J.N.,Forman, M.,Gilbert, E.J.,Hodgson, R.A.,Hyde, L.A.,Jiang, Q.,Iserloh, U.,Kazakevich, I.,Kuvelkar, R.,Mei, H.,Meredith, J.,Misiaszek, J.,Orth, P.,Rossiter, L.M.,Slater, M.,Stone, J.,Strickland, C.O.,Voigt, J.H.,Wang, G.,Wang, H.,Wu, Y.,Greenlee, W.J.,Parker, E.M.,Kennedy, M.E.,Stamford, A.W.
Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.
J. Med. Chem., 59:10435-10450, 2016

PubMed Abstract: Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

PubMed: 27933948
DOI: 10.1021/acs.jmedchem.6b00307

実験手法

X-RAY DIFFRACTION (1.5 Å)