6JT3

Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide

6JT3 の概要

• エントリーDOI: 10.2210/pdb6jt3/pdb
• 分子名称: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: gs-hbace1(43-454), hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47242.51

構造登録者

Tadano, G.,Komano, K.,Yoshida, S.,Suzuki, S.,Nakahara, K.,Fuchino, K.,Fujimoto, K.,Matsuoka, E.,Yamamoto, T.,Asada, N.,Ito, H.,Sakaguchi, G.,Kanegawa, N.,Kido, Y.,Ando, S.,Fukushima, T.,Teisman, A.,Urmaliya, V.,Dhuyvetter, D.,Borghys, H.,Bergh, A.V.D.,Austin, N.,Gijsen, H.J.M.,Yamano, Y.,Iso, Y.,Kusakabe, K.I. (登録日: 2019-04-08, 公開日: 2019-10-30, 最終更新日: 2024-11-06)

主引用文献

Tadano, G.,Komano, K.,Yoshida, S.,Suzuki, S.,Nakahara, K.,Fuchino, K.,Fujimoto, K.,Matsuoka, E.,Yamamoto, T.,Asada, N.,Ito, H.,Sakaguchi, G.,Kanegawa, N.,Kido, Y.,Ando, S.,Fukushima, T.,Teisman, A.,Urmaliya, V.,Dhuyvetter, D.,Borghys, H.,Van Den Bergh, A.,Austin, N.,Gijsen, H.J.M.,Yamano, Y.,Iso, Y.,Kusakabe, K.I.
Discovery of an Extremely Potent Thiazine-Based beta-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose.
J.Med.Chem., 62:9331-9337, 2019

PubMed Abstract: Genetic evidence points to deposition of amyloid-β (Aβ) as a causal factor for Alzheimer's disease. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead , we describe the discovery of a thiazine-based BACE1 inhibitor with robust Aβ reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where achieved sustained Aβ reduction of 80% at trough level.

PubMed: 31549838
DOI: 10.1021/acs.jmedchem.9b01140

実験手法

X-RAY DIFFRACTION (2.4 Å)