6WNY

Crystal structure of BACE1 in complex with (Z)-fluoro-olefin containing compound 15

Summary for 6WNY

• Entry DOI: 10.2210/pdb6wny/pdb
• Descriptor: Beta-secretase 1, 6-[(Z)-2-{3-[(1S,5S,6S)-3-amino-5-methyl-1-(morpholine-4-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl}-1-fluoroethenyl]pyridine-3-carbonitrile, IODIDE ION, ... (4 entities in total)
• Functional Keywords: aspartic protease, amyloid precursor protein, app, alzheimer's disease, inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 46698.70

Authors

Whittington, D.A. (deposition date: 2020-04-23, release date: 2020-06-03, Last modification date: 2024-11-20)

Primary citation

Frohn, M.,Liu, L.,Siegmund, A.C.,Qian, W.,Amegadzie, A.,Chen, N.,Tan, H.,Hickman, D.,Wood, S.,Wen, P.H.,Bartberger, M.D.,Whittington, D.A.,Allen, J.R.,Bourbeau, M.P.
The development of a structurally distinct series of BACE1 inhibitors via the (Z)-fluoro-olefin amide bioisosteric replacement.
Bioorg.Med.Chem.Lett., 30:127240-127240, 2020

PubMed Abstract: The (Z)-fluoro-olefin amide bioisosteric replacement is an effective tool for addressing various shortcomings of the parent amide. In an effort to fine tune ADME properties of BACE1 preclinical candidate AM-6494, a series of structurally distinct (Z)-fluoro-olefin containing analogs was developed that culminated in compound 15. Herein, we detail design considerations, synthetic challenges, structure activity relationship (SAR) studies, and in vivo properties of an advanced compound in this novel series of BACE1 inhibitors.

PubMed: 32527542
DOI: 10.1016/j.bmcl.2020.127240

Experimental method

X-RAY DIFFRACTION (1.86 Å)