Using our previously validated oxadiazine moiety as the suitable isosteric replacement of amide functionality, several structurally differentiated leads were designed, synthesized and validated as the modulators of γ-Secretase enzyme for the potential treatment of Alzheimer’s disease. The oxadiazines with substitutions at both 3 and 4 positions represented as 1, designed to limit conformational plasticity, robustly lowered the CSF Aβ42 upon oral dosing. To further diversify the structure and to mitigate the concern related to exocyclic double bond presents in 1, novel endo cyclic β, β-disubstituted framework, represented as 2 was designed for the γ-Secretase modulation in vivo to lower Aβ42 in CSF upon oral dosing.

Generation of novel leads for γ-secretase modulation

253rd National Meeting (2017)

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