Abstract
SAR of a novel series of pyridine-derived γ-secretase modulators is described. Compound 5 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain (or increase) the levels of total Aβ. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aβ42 in the brain without altering Notch processing in the peripheral.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
-
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
-
Animals
-
Biological Availability
-
Cytochrome P-450 Enzyme Inhibitors
-
Dose-Response Relationship, Drug
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology*
-
Humans
-
Molecular Structure
-
Pyridines / chemical synthesis
-
Pyridines / chemistry
-
Pyridines / pharmacology*
-
Rats
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
Cytochrome P-450 Enzyme Inhibitors
-
Enzyme Inhibitors
-
Pyridines
-
Amyloid Precursor Protein Secretases
-
pyridine