5CLM

1,4-Oxazine BACE1 inhibitors

5CLM の概要

• エントリーDOI: 10.2210/pdb5clm/pdb
• 分子名称: Beta-secretase 1, N-{3-[(3R)-5-amino-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl]phenyl}-5-chloropyridine-2-carboxamide, IODIDE ION, ... (5 entities in total)
• 機能のキーワード: bace1 protease inhibitor, orally bioavailable, brain penetrant, proteros biostructures gmbh, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P56817
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45389.01

構造登録者

Rombouts, F.,Tresadern, G.,Delgado, O.,Martinez Lamenca, C.,Van Gool, M.,Garcia-Molina, A.,Alonso De Diego, S.,Oehlrich, D.,Prokopcova, H.,Alonso, J.M.,Austin, N.,Borghys, H.,Van Brandt, S.,Surkyn, M.,De Cleyn, M.,Vos, A.,Alexander, R.,MacDonald, G.,Moechars, D.,Trabanco, A.,Gijsen, H. (登録日: 2015-07-16, 公開日: 2015-09-30, 最終更新日: 2024-10-23)

主引用文献

Rombouts, F.J.,Tresadern, G.,Delgado, O.,Martinez-Lamenca, C.,Van Gool, M.,Garcia-Molina, A.,Alonso de Diego, S.A.,Oehlrich, D.,Prokopcova, H.,Alonso, J.M.,Austin, N.,Borghys, H.,Van Brandt, S.,Surkyn, M.,De Cleyn, M.,Vos, A.,Alexander, R.,Macdonald, G.,Moechars, D.,Gijsen, H.,Trabanco, A.A.
1,4-Oxazine beta-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.
J.Med.Chem., 58:8216-8235, 2015

PubMed Abstract: 1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.

PubMed: 26378740
DOI: 10.1021/acs.jmedchem.5b01101

実験手法

X-RAY DIFFRACTION (2.61 Å)