Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease

• Published in: Journal of medicinal chemistry 2020-06, Vol.63 (11), p.6028-6056
• Main Authors: Šála, Michal, Hollinger, Kristen R, Thomas, Ajit G, Dash, Ranjeet P, Tallon, Carolyn, Veeravalli, Vijayabhaskar, Lovell, Lyndah, Kögler, Martin, Hřebabecký, Hubert, Procházková, Eliška, Nešuta, Ondřej, Donoghue, Amanda, Lam, Jenny, Rais, Rana, Rojas, Camilo, Slusher, Barbara S, Nencka, Radim
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Animals; Body Weight - drug effects; Brain - metabolism; Disease Models, Animal; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Exosomes - metabolism; Female; Humans; Male; Mice; Mice, Transgenic; Pyridazines - chemistry; Pyridazines - metabolism; Pyridazines - therapeutic use; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelin Phosphodiesterase - metabolism; Sphingomyelin Phosphodiesterase - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00278

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 have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl ( )-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2- ]pyridazin-8-yl)pyrrolidin-3-yl)carbamate , the first nSMase2 inhibitor that 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 the efficacy of in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogues, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.