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.