Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors.

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (−)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer’s disease. Specifically, 4-CF3 and 4-Br substituted arylsulfone analogs, (−)-1b and (−)-1c, are equipotent to compound (−)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.