| Literature DB >> 19432431 |
Linda E Keown1, Ian Collins, Laura C Cooper, Timothy Harrison, Andrew Madin, Jayesh Mistry, Michael Reilly, Mohamed Shaimi, Christopher J Welch, Earl E Clarke, Huw D Lewis, Jonathan D J Wrigley, Jonathan D Best, Fraser Murray, Mark S Shearman.
Abstract
The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED(50) of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.Entities:
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Year: 2009 PMID： 19432431 DOI： 10.1021/jm900056p
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446