7MYI

BACE-1 in complex with compound #6

7MYI の概要

• エントリーDOI: 10.2210/pdb7myi/pdb
• 分子名称: Beta-secretase 1, (4aR,7aR)-6-(pyrimidin-2-yl)-7a-(thiophen-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-amine, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 98759.29

構造登録者

Hendle, J.,Timm, D.E.,Stout, S.L. (登録日: 2021-05-21, 公開日: 2021-07-21, 最終更新日: 2024-11-06)

主引用文献

McKinzie, D.L.,Winneroski, L.L.,Green, S.J.,Hembre, E.J.,Erickson, J.A.,Willis, B.A.,Monk, S.A.,Aluise, C.D.,Baker, T.K.,Lopez, J.E.,Hendle, J.,Beck, J.P.,Brier, R.A.,Boggs, L.N.,Borders, A.R.,Cocke, P.J.,Garcia-Losada, P.,Lowe, S.L.,Mathes, B.M.,May, P.C.,Porter, W.J.,Stout, S.L.,Timm, D.E.,Watson, B.M.,Yang, Z.,Mergott, D.J.
Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.
J.Med.Chem., 64:8076-8100, 2021

PubMed Abstract: The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.

PubMed: 34081466
DOI: 10.1021/acs.jmedchem.1c00489

実験手法

X-RAY DIFFRACTION (1.25 Å)