- Novel orally bioavailable γ-secretase inhibitors with excellent in vivo activity
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The development of potent γ-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-β in APP-YAC mice with an ED50 of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.
- Keown, Linda E.,Collins, Ian,Cooper, Laura C.,Harrison, Timothy,Madin, Andrew,Mistry, Jayesh,Reilly, Michael,Shaimi, Mohamed,Welch, Christopher J.,Clarke, Earl E.,Lewis, Huw D.,Wrigley, Jonathan D. J.,Best, Jonathan D.,Murray, Fraser,Shearman, Mark S.
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supporting information; experimental part
p. 3441 - 3444
(2010/03/30)
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- HETEROARYL SUBSTITUTED SPIROCYCLIC SULFAMIDES FOR INHIBITION OF GAMMA SECRETASE
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Compounds of formula I are disclosed: in which X is a 5-membered heteroaryl ring and R is as defined herein. The compounds are inhibitors of the processing of APP by gamma-secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.
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Page/Page column 111
(2008/06/13)
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