Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease
Tina Bilousova, Bryan J. Simmons, Rachel R. Knapp, Chris Jean Elias, Jesus Campagna, Mikhail Melnik, Sujyoti Chandra, Samantha Focht, Chunni Zhu, Kanagasabai Vadivel, Barbara Jagodzinska, Whitaker Cohn, Patricia Spilman, Karen H. Gylys, Neil K. Garg, Varghese John
Abstract
We report the discovery of a novel class of compounds that function as dual inhibitors of the enzymes neutral sphingomyelinase-2 (nSMase2) and acetylcholinesterase (AChE). Inhibition of these enzymes provides a unique strategy to suppress the propagation of tau pathology in the treatment of Alzheimer’s disease (AD). We describe the key SAR elements that affect relative nSMase2 and/or AChE inhibitor effects and potency, in addition to the identification of two analogs that suppress the release of tau-bearing exosomes in vitro and in vivo . Identification of these novel dual nSMase2/AChE inhibitors represents a new therapeutic approach to AD and has the potential to lead to the development of truly disease-modifying therapeutics.