Abstract
SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain the levels of total Aβ. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid beta-Peptides / metabolism
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Animals
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Cell Survival
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Cells, Cultured
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Enzyme Activation / drug effects
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Humans
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Inhibitory Concentration 50
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Pyridazines / chemical synthesis*
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Pyridazines / chemistry
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Pyridazines / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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Amyloid beta-Peptides
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Pyridazines
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pyridazine
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Amyloid Precursor Protein Secretases