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

0525539 - ÚOCHB 2021 RIV US eng J - Journal Article
Šála, Michal - Hollinger, K. R. - Thomas, A. G. - Dash, R. P. - Tallon, C. - Veeravalli, V. - Lovell, L. - Kögler, Martin - Hřebabecký, Hubert - Procházková, Eliška - Nešuta, Ondřej - Donoghue, A. - Lam, J. - Rais, R. - Rojas, C. - Slusher, B. S. - Nencka, Radim
Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease.
Journal of Medicinal Chemistry. Roč. 63, č. 11 (2020), s. 6028-6056. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : cognitive impairment * in vivo * metabolism
OECD category: Organic chemistry
Impact factor: 7.446, year: 2020
Method of publishing: Limited access
https://pubs.acs.org/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 (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 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 1 (PDDC) 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.
Permanent Link: http://hdl.handle.net/11104/0309645