Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives as γ-secretase modulators.

Abstract Novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3- a ]pyridine derivatives were designed, synthesized, and evaluated as γ-secretase modulators (GSMs). An optimization study of this series resulted in the identification of ( R )- 11j , which showed a potent Aβ 42 -lowering effect, high bioavailability and good blood–brain barrier permeability in mice. Oral administration of ( R )- 11j significantly reduced brain Aβ 42 in mice at a dose of 10 mg/kg.