5YGY

Crystal Structure of BACE1 in complex with (S)-N-(3-(2-amino-6-(fluoromethyl)-4 -methyl-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide

5YGY の概要

• エントリーDOI: 10.2210/pdb5ygy/pdb
• 分子名称: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: beta-site amyloid precursor protein cleaving enzyme 1, 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: 47687.20

構造登録者

Fuchino, K.,Mitsuoka, Y.,Masui, M.,Kurose, N.,Yoshida, S.,Komano, K.,Yamamoto, T.,Ogawa, M.,Unemura, C.,Hosono, M.,Ito, H.,Sakaguchi, G.,Ando, S.,Ohnishi, S.,Kido, Y.,Fukushima, T.,Miyajima, H.,Hiroyama, S.,Koyabu, K.,Dhuyvetter, D.,Borghys, H.,Gijsen, H.,Yamano, Y.,Iso, Y.,Kusakabe, K. (登録日: 2017-09-27, 公開日: 2018-05-23, 最終更新日: 2024-11-13)

主引用文献

Fuchino, K.,Mitsuoka, Y.,Masui, M.,Kurose, N.,Yoshida, S.,Komano, K.,Yamamoto, T.,Ogawa, M.,Unemura, C.,Hosono, M.,Ito, H.,Sakaguchi, G.,Ando, S.,Ohnishi, S.,Kido, Y.,Fukushima, T.,Miyajima, H.,Hiroyama, S.,Koyabu, K.,Dhuyvetter, D.,Borghys, H.,Gijsen, H.J.M.,Yamano, Y.,Iso, Y.,Kusakabe, K.I.
Rational Design of Novel 1,3-Oxazine Based beta-Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P-gp Efflux Leading to Robust A beta Reduction in the Brain
J. Med. Chem., 61:5122-5137, 2018

PubMed Abstract: Accumulation of Aβ peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. β-Secretase (BACE1) is a key enzyme responsible for producing Aβ peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a p K lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aβ reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models. This compound improved the brain-to-plasma ratio relative to 6 by reducing P-gp recognition, which was demonstrated by a P-gp knockout mouse model.

PubMed: 29733614
DOI: 10.1021/acs.jmedchem.8b00002

実験手法

X-RAY DIFFRACTION (2.3 Å)