Discovery of the Oxadiazine FRM-024: A Potent CNS-Penetrant Gamma Secretase Modulator

The
recent approval of aducanumab for Alzheimer’s disease
has heightened the interest in therapies targeting the amyloid hypothesis.
Our research has focused on identification of novel compounds to improve
amyloid processing by modulating gamma secretase activity, thereby
addressing a significant biological deficit known to plague the familial
form of the disease. Herein, we describe the design, synthesis, and
optimization of new gamma secretase modulators (GSMs) based on previously
reported oxadiazine 1. Potency improvements with a focus
on predicted and measured properties afforded high-quality compounds
further differentiated via robust Aβ42 reductions
in both rodents and nonhuman primates. Extensive preclinical profiling,
efficacy studies, and safety studies resulted in the nomination of
FRM-024, (+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-(6-methoxy-5-(4-methyl-1H-imidazole-1-yl)­pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine, as a GSM preclinical candidate for familial Alzheimer’s
disease.