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Design, Synthesis, and Evaluation of a Novel Series of Oxadiazine Gamma Secretase Modulators for Familial Alzheimer’s Disease
Herein we describe the design, synthesis,
and evaluation of a novel
series of oxadiazine-based gamma secretase modulators obtained via
isosteric amide replacement and critical consideration of conformational
restriction. Oxadiazine lead <b>47</b> possesses good in vitro
potency with excellent predicted CNS drug-like properties and desirable
ADME/PK profile. This lead compound demonstrated robust Aβ<sub>42</sub> reductions and subsequent Aβ<sub>37</sub> increases
in both rodent brain and CSF at 30 mg/kg dosed orally