Design and discovery of C2-fluoroalkyl iminothiazine dioxides as BACE inhibitors

[Display omitted] This paper describes the structure–activity-relationships of novel fluoroalkyl substituents at the C2 position of iminothiazine dioxide beta secretase inhibitors. Key discoveries include reduced amidine basicity and its effect on Pgp, cell potency, and efficacy in various preclinic...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 56; p. 128463
Main Authors:	Taoka, Brandon M., Wu, Wen-Lian, Hao, Jinsong, Dolmaski, Martin, Wang, Hongwu, Levorse, Dorothy, Orth, Peter, Hyde, Lynn A., Smith, Brad, Michener, Maria S., Kennedy, Matthew E., Parker, Eric M., Cumming, Jared N.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 15-01-2022
Subjects:	Administration, Oral Alzheimer's disease Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - metabolism Animals Aspartic Acid Endopeptidases - antagonists & inhibitors Aspartic Acid Endopeptidases - metabolism BACE-1 Beta-secretase-1 inhibitor CNS Dose-Response Relationship, Drug Drug Discovery Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology HEK293 Cells Humans Molecular Structure Oxides - administration & dosage Oxides - chemistry Oxides - pharmacology Rats Structure-Activity Relationship Thiazines - administration & dosage Thiazines - chemistry Thiazines - pharmacology CNS Beta-secretase-1 inhibitor Alzheimer's disease BACE-1
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Summary:	[Display omitted] This paper describes the structure–activity-relationships of novel fluoroalkyl substituents at the C2 position of iminothiazine dioxide beta secretase inhibitors. Key discoveries include reduced amidine basicity and its effect on Pgp, cell potency, and efficacy in various preclinical in vivo efficacy animal models. Findings from these structure–activity-relationships are discussed.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2021.128463