Discovery of BIIB042, a potent, selective, and orally bioavailable γ-secretase modulator

…, T Talreja, Z Xin, JH Cuervo, G Kumaravel…

Index: 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. ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 10 p. 786 - 791

Full Text: HTML

Citation Number: 12

Abstract

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 ...