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ID: ALA3085750
Journal: Bioorg Med Chem Lett
Title: Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer's disease.
Authors: Chen JJ, Qian W, Biswas K, Yuan C, Amegadzie A, Liu Q, Nixey T, Zhu J, Ncube M, Rzasa RM, Chavez F, Chen N, DeMorin F, Rumfelt S, Tegley CM, Allen JR, Hitchcock S, Hungate R, Bartberger MD, Zalameda L, Liu Y, McCarter JD, Zhang J, Zhu L, Babu-Khan S, Luo Y, Bradley J, Wen PH, Reid DL, Koegler F, Dean C, Hickman D, Correll TL, Williamson T, Wood S.
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 GSM lead. 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 potency is described.
CiteXplore: 24139583