Abstract
Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as β-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 μΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / chemistry
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry
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Blood-Brain Barrier / metabolism
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Cell Line
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Dogs
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Drug Design
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Drug Evaluation, Preclinical
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Humans
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Naphthalenes / chemical synthesis*
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Naphthalenes / chemistry
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Naphthalenes / metabolism
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Permeability
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / metabolism
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Structure-Activity Relationship
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Thiadiazines / chemical synthesis*
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Thiadiazines / chemistry
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Thiadiazines / metabolism
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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N-(3-(2-amino-6H-1,3,4-thiadiazin-5-yl)-4-(benzyloxy)phenyl)-1-naphthamide hydrobromide
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Naphthalenes
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Protease Inhibitors
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Thiadiazines
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human