| Literature DB >> 24900267 |
Hairuo Peng1, Tina Talreja1, Zhili Xin1, J Hernan Cuervo1, Gnanasambandam Kumaravel1, Michael J Humora1, Lin Xu1, Ellen Rohde1, Lawrence Gan1, Mi-Young Jung1, Melanie N Shackett1, Sowmya Chollate1, Anthone W Dunah1, Pamela A Snodgrass-Belt1, H Moore Arnold1, Arthur G Taveras1, Kenneth J Rhodes1, Robert H Scannevin1.
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 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.Entities:
Keywords: Alzheimer's; GSM; Mannich reaction; Secretase; amyloid
Year: 2011 PMID： 24900267 PMCID： PMC4018072 DOI： 10.1021/ml200175q
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345