Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer's disease.
2013
Abstract γ-Secretase modulators (
GSMs) are potentially disease-modifying treatments for Alzheimer’s disease. They selectively lower pathogenic Aβ42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a
GSMlead. Lead optimization studies identified compound 25 with improved
cell potency, PKDM properties, and it lowered Aβ42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular
potencyis described.
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