5YGX

Structure of BACE1 in complex with N-(3-((4R,5R,6S)-2-amino-6-(1,1-difluoroethyl)-5-fluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide

5YGX の概要

• エントリーDOI: 10.2210/pdb5ygx/pdb
• 分子名称: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: beta secretase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 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: 47644.82

構造登録者

Nakahara, K.,Fuchino, K.,Komano, K.,Asada, N.,Tadano, G.,Hasegawa, T.,Yamamoto, T.,Sako, Y.,Ogawa, M.,Unemura, C.,Hosono, M.,Sakaguchi, G.,Ando, S.,Ohnishi, S.,Kido, Y.,Fukushima, T.,Dhuyvetter, D.,Borghys, H.,Gijsen, H.,Yamano, Y.,Iso, Y.,Kusakabe, K. (登録日: 2017-09-27, 公開日: 2018-08-08, 最終更新日: 2024-11-20)

主引用文献

Nakahara, K.,Fuchino, K.,Komano, K.,Asada, N.,Tadano, G.,Hasegawa, T.,Yamamoto, T.,Sako, Y.,Ogawa, M.,Unemura, C.,Hosono, M.,Ito, H.,Sakaguchi, G.,Ando, S.,Ohnishi, S.,Kido, Y.,Fukushima, T.,Dhuyvetter, D.,Borghys, H.,Gijsen, H.J.M.,Yamano, Y.,Iso, Y.,Kusakabe, K.I.
Discovery of Potent and Centrally Active 6-Substituted 5-Fluoro-1,3-dihydro-oxazine beta-Secretase (BACE1) Inhibitors via Active Conformation Stabilization
J. Med. Chem., 61:5525-5546, 2018

PubMed Abstract: β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in 24 with robust Aβ reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency.

PubMed: 29775538
DOI: 10.1021/acs.jmedchem.8b00011

実験手法

X-RAY DIFFRACTION (2.2 Å)