6UVP

BACE-1 in complex with compound #3

Summary for 6UVP

• Entry DOI: 10.2210/pdb6uvp/pdb
• Descriptor: Beta-secretase 1, N-{(1S,2S)-2-[(4aS,7aR)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]cyclopropyl}-5-fluoropyridine-2-carboxamide, N-{(1R,2R)-2-[(4aS,7aR)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]cyclopropyl}-5-fluoropyridine-2-carboxamide, ... (6 entities in total)
• Functional Keywords: protease, inhibitor, complex, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 100615.10

Authors

Hendle, J.,Timm, D.E. (deposition date: 2019-11-04, release date: 2019-12-11, Last modification date: 2024-10-23)

Primary citation

Winneroski, L.L.,Erickson, J.A.,Green, S.J.,Lopez, J.E.,Stout, S.L.,Porter, W.J.,Timm, D.E.,Audia, J.E.,Barberis, M.,Beck, J.P.,Boggs, L.N.,Borders, A.R.,Boyer, R.D.,Brier, R.A.,Hembre, E.J.,Hendle, J.,Garcia-Losada, P.,Minguez, J.M.,Mathes, B.M.,May, P.C.,Monk, S.A.,Rankovic, Z.,Shi, Y.,Watson, B.M.,Yang, Z.,Mergott, D.J.
Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints.
Bioorg.Med.Chem., 28:115194-115194, 2020

PubMed Abstract: Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.

PubMed: 31786008
DOI: 10.1016/j.bmc.2019.115194

Experimental method

X-RAY DIFFRACTION (1.56 Å)