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Novel human neutral sphingomyelinase 2 inhibitors as potential therapeutics for Alzheimer disease.

Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release has been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b] pyridazin-8-yl) pyrrolidin-3-yl)-carbamate 1 (PDDC), the first nSMase2 inhibitor which possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogs, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.