TY - JOUR
T1 - Novel orally bioavailable γ-secretase inhibitors with excellent in vivo activity
AU - Keown, Linda E.
AU - Collins, Ian
AU - Cooper, Laura C.
AU - Harrison, Timothy
AU - Madin, Andrew
AU - Mistry, Jayesh
AU - Reilly, Michael
AU - Shaimi, Mohamed
AU - Welch, Christopher J.
AU - Clarke, Earl E.
AU - Lewis, Huw D.
AU - Wrigley, Jonathan D J
AU - Best, Jonathan D.
AU - Murray, Fraser
AU - Shearman, Mark S.
PY - 2009/6/11
Y1 - 2009/6/11
N2 - 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. © 2009 American Chemical Society.
AB - 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. © 2009 American Chemical Society.
U2 - 10.1021/jm900056p
DO - 10.1021/jm900056p
M3 - Article
C2 - 19432431
SN - 0022-2623
VL - 52
SP - 3441
EP - 3444
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -
