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

Article abstract of DOI:10.1021/jm900056p

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.