Discovery of a Tetrahydrobenzisoxazole Series of γ-Secretase Modulators

The design and synthesis of a new series of tetrahydrobenzisoxazoles as modulators of γ-secretase activity and their structure–activity relationship (SAR) will be detailed. Several compounds are active γ-secretase modulators (GSMs) with good to excellent selectivity for the reduction of Aβ42 in the cellular assay. Compound 14a was tested in vivo in a nontransgenic rat model and was found to significantly reduce Aβ42 in the CNS compartment compared to vehicle-treated animals (up to 58% reduction of cerebrospinal fluid Aβ42 as measured 3 h after an acute oral dosing at 30 mg/kg).