141258-14-2Relevant articles and documents
Discovery of BIIB042, a potent, selective, and orally bioavailable γ-secretase modulator
Peng, Hairuo,Talreja, Tina,Xin, Zhili,Cuervo, J. Hernan,Kumaravel, Gnanasambandam,Humora, Michael J.,Xu, Lin,Rohde, Ellen,Gan, Lawrence,Jung, Mi-Young,Shackett, Melanie N.,Chollate, Sowmya,Dunah, Anthone W.,Snodgrass-Belt, Pamela A.,Arnold, H. Moore,Taveras, Arthur G.,Rhodes, Kenneth J.,Scannevin, Robert H.
supporting information; experimental part, p. 786 - 791 (2011/12/02)
We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.
CARBOXYLIC ACID-CONTAINING COMPOUNDS, DERIVATIVES THEREOF, AND RELATED METHODS OF USE
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Page/Page column 110, (2010/12/26)
Compounds that modulate gamma secretase (e.g., alter the cleavage pattern of gamma secretase) are described herein. Also disclosed are pharmaceutical compositions, methods of modulating the activity of gamma secretase, and methods of treating Alzheimer's Disease using the compounds described herein.
