Identification of next generation gamma-secretase modulators for Alzheimer's disease

Abstract Alzheimer’s disease (AD) is the most common form of senile dementia. An estimated 6 million Americans are affected, and this number is increasing yearly. Currently, there is no cure for AD; however, it is widely accepted that inhibiting amyloid plaque formation would be beneficial for the prevention of Alzheimer’s disease. Although there are many approaches for the treatment of AD, one novel and innovative approach is to modulate the activity of the key enzyme complex involved in Aβ42 production (a primary component of amyloid plaques), γ-secretase (GS). Because of the potential for serious side-effects associated with inhibition of GS, modulation of its activity was targeted in order to avoid non-specific effects on other γ-secretase substrates such as the Notch, an essential element for normal cellular development. Our scientific approach will focus on the next generation of γ-secretase modulators (GSMs), identified and selected based while using ligand and structural based drug design. Medicinal chemistry followed by in vitro and in vivo optimization efforts will lead to the identification of novel lead compounds with lowering of Aβ42 both in vitro and in vivo while promoting the formation of smaller, potentially less toxic Aβ peptides (Aβ37 and Aβ38) without altering the activity of γ−secretase toward other substrates such as Notch. In this proposal, we plan to identify compounds for modulating Aβ peptides with excellent absorption, distribution, metabolism, and safety properties to gain a large therapeutic index. These studies are expected to aid in the choice of a candidate to pursue pre-clinical studies. 1