4FRS

Structure of BACE in complex with (S)-4-(3-chloro-5-(5-(prop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-1,4-dimethyl-6-oxotetrahydropyrimidin-2(1H)-iminium

4FRS の概要

• エントリーDOI: 10.2210/pdb4frs/pdb
• 関連するPDBエントリー: 4DJU 4DJV 4DJW 4DJX 4DJY
• 分子名称: Beta-secretase 1, (2Z,6S)-6-{3-chloro-5-[5-(prop-1-yn-1-yl)pyridin-3-yl]thiophen-2-yl}-2-imino-3,6-dimethyltetrahydropyrimidin-4(1H)-one (3 entities in total)
• 機能のキーワード: alzheimer's, aspartyl protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 2
• 化学式量合計: 88793.00

構造登録者

Orth, P. (登録日: 2012-06-26, 公開日: 2012-08-08, 最終更新日: 2024-11-20)

主引用文献

Stamford, A.W.,Scott, J.D.,Li, S.W.,Babu, S.,Tadesse, D.,Hunter, R.,Wu, Y.,Misiaszek, J.,Cumming, J.N.,Gilbert, E.J.,Huang, C.,McKittrick, B.A.,Hong, L.,Guo, T.,Zhu, Z.,Strickland, C.,Orth, P.,Voigt, J.H.,Kennedy, M.E.,Chen, X.,Kuvelkar, R.,Hodgson, R.,Hyde, L.A.,Cox, K.,Favreau, L.,Parker, E.M.,Greenlee, W.J.
Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS A(beta) Reduction
ACS Med Chem Lett, 3:897-902, 2012

PubMed Abstract: Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.

PubMed: 23412139
DOI: 10.1021/ml3001165

実験手法

X-RAY DIFFRACTION (1.7 Å)