Novel orally bioavailable gamma-secretase inhibitors with excellent in vivo activity

J Med Chem. 2009 Jun 11;52(11):3441-4. doi: 10.1021/jm900056p.

Linda E Keown ¹, 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

Affiliations

Affiliation

1 Department of Medicinal Chemistry, Molecular and Cellular Neuroscience, and in Vivo Neuroscience, The Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park, Harlow, Essex, UK. keown.linda@yahoo.co.uk

PMID: 19432431 DOI: 10.1021/jm900056p

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.

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