Abstract
The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30 mg/kg oral dose.
Keywords:
Alzheimer’s disease; Aβ42 reduction; Gamma secretase modulators; Tetrahydroindazoles.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Amyloid Precursor Protein Secretases / chemistry
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Amyloid Precursor Protein Secretases / metabolism*
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / metabolism
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Animals
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Bridged Bicyclo Compounds / chemistry
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Cells, Cultured
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Drug Design
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Drug Evaluation, Preclinical
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Female
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Half-Life
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Imidazoles / chemical synthesis
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Imidazoles / chemistry*
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Imidazoles / pharmacokinetics
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Inhibitory Concentration 50
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Rats
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Rats, Wistar
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Structure-Activity Relationship
Substances
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Amyloid beta-Peptides
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Bridged Bicyclo Compounds
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Imidazoles
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imidazole
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Amyloid Precursor Protein Secretases