6JT4

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

6JT4 の概要

• エントリーDOI: 10.2210/pdb6jt4/pdb
• 分子名称: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (5 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: 47419.35

構造登録者

Anan, K.,Iso, Y.,Oguma, T.,Nakahara, K.,Suzuki, S.,Yamamoto, T.,Matsuoka, E.,Ito, H.,Sakaguchi, G.,Ando, S.,Morimoto, K.,Kanegawa, N.,Kido, Y.,Kawachi, T.,Fukushima, T.,Teisman, A.,Urmaliya, V.,Dhuyvetter, D.,Borghys, H.,Austin, N.,Bergh, A.V.D.,Verboven, P.,Bischoff, F.,Gijsen, H.J.M.,Yamano, Y.,Kusakabe, K.I. (登録日: 2019-04-08, 公開日: 2020-01-15, 最終更新日: 2024-10-23)

主引用文献

Anan, K.,Iso, Y.,Oguma, T.,Nakahara, K.,Suzuki, S.,Yamamoto, T.,Matsuoka, E.,Ito, H.,Sakaguchi, G.,Ando, S.,Morimoto, K.,Kanegawa, N.,Kido, Y.,Kawachi, T.,Fukushima, T.,Teisman, A.,Urmaliya, V.,Dhuyvetter, D.,Borghys, H.,Austin, N.,Van Den Bergh, A.,Verboven, P.,Bischoff, F.,Gijsen, H.J.M.,Yamano, Y.,Kusakabe, K.
Trifluoromethyl Dihydrothiazine-Based beta-Secretase (BACE1) Inhibitors with Robust Central beta-Amyloid Reduction and Minimal Covalent Binding Burden.
Chemmedchem, 14:1894-1910, 2019

PubMed Abstract: The β-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as β-secretase) is a promising target for the treatment of Alzheimer's disease. A pK lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aβ reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [ C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound.

PubMed: 31657130
DOI: 10.1002/cmdc.201900478

実験手法

X-RAY DIFFRACTION (2.2 Å)