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

Summary for 6JT3

• Entry DOI: 10.2210/pdb6jt3/pdb
• Descriptor: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: gs-hbace1(43-454), hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 47242.51

Authors

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. (deposition date: 2019-04-08, release date: 2019-10-30, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)