7MYI

BACE-1 in complex with compound #6

Summary for 7MYI

• Entry DOI: 10.2210/pdb7myi/pdb
• Descriptor: 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)
• Functional Keywords: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 98759.29

Authors

Hendle, J.,Timm, D.E.,Stout, S.L. (deposition date: 2021-05-21, release date: 2021-07-21, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.25 Å)