Discovery of Potent and Centrally Active 6-Substituted 5-Fluoro-1,3-dihydro-oxazine β-Secretase (BACE1) Inhibitors via Active Conformation Stabilization

Journal of Medicinal Chemistry
Kenji NakaharaKen-Ichi Kusakabe

Abstract

β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in 24 with robust Aβ reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency.

References

Nov 24, 1999·Molecular and Cellular Neurosciences·I HussainG Christie
Mar 4, 2000·Proceedings of the National Academy of Sciences of the United States of America·X LinJ Tang
Aug 10, 2000·Proceedings of the National Academy of Sciences of the United States of America·M FarzanH Choe
Aug 20, 2009·Current Medicinal Chemistry·Bertrand Le Bourdonnec, Lara K Leister
Jan 29, 2010·The New England Journal of Medicine·Henry W Querfurth, Frank M LaFerla
Apr 28, 2010·Chemical Reviews·MaryAnn T RobakJonathan A Ellman
Dec 15, 2010·Journal of Medicinal Chemistry·Daniel OehlrichHarrie J M Gijsen
Aug 20, 2011·Nature Reviews. Drug Discovery·Eric KarranBart De Strooper
Sep 13, 2011·Cell Metabolism·Daria EsterházyMarkus Stoffel
Nov 18, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Patrick C MayJames E Audia
Oct 11, 2012·The Journal of Biological Chemistry·Fredrik JeppssonJohanna Fälting
Jun 6, 2013·Bioorganic & Medicinal Chemistry Letters·Thomas J WolteringRobert Narquizian
Jun 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Leila RochinGuillaume van Niel
Feb 22, 2014·Lancet Neurology·Riqiang Yan, Robert Vassar
Apr 3, 2014·Chemical Society Reviews·Arun K Ghosh, Heather L Osswald
Apr 8, 2014·Bioorganic & Medicinal Chemistry Letters·Daniel OehlrichHarrie J M Gijsen
Dec 17, 2014·Journal of Medicinal Chemistry·Zoran Rankovic
Jan 23, 2015·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Patrick C MayDustin J Mergott
Jul 23, 2015·Journal of Medicinal Chemistry·Eric P GillisNicholas A Meanwell
Sep 18, 2015·Journal of Medicinal Chemistry·Frederik J R RomboutsAndrés A Trabanco
Feb 19, 2016·Journal of Alzheimer's Disease : JAD·Susanna EketjällGvido Cebers
Mar 24, 2016·Journal of Medicinal Chemistry·Matthew G BursavichJean-François Blain
Aug 24, 2016·Alzheimer's & Dementia : Translational Research & Clinical Interventions·Maarten TimmersJohannes Rolf Streffer

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Citations

Oct 5, 2019·Chemical Biology & Drug Design·Dhafer S ZinadMohammad Rizki Fadhil Pratama
Feb 6, 2020·Angewandte Chemie·Marco Reichel, Konstantin Karaghiosoff
Sep 22, 2020·Beilstein Journal of Organic Chemistry·Benjamin JeffriesBruno Linclau
Jan 26, 2021·Physical Chemistry Chemical Physics : PCCP·Cristian PrivatJaime Rubio-Martinez
Oct 3, 2020·Expert Opinion on Therapeutic Patents·Frederik RomboutsHarrie J M Gijsen
Dec 22, 2019·Journal of Molecular Biology·Andrey AlekseenkoDima Kozakov
May 21, 2020·Journal of Medicinal Chemistry·Matthew D Lloyd

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