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

Michal Šála, Kristen R. Hollinger, Kristen Hollinger, Kristen Hollinger, Ajit G. Thomas, Ranjeet P. Dash, Carolyn Tallon, Carolyn Tallon, Vijayabhaskar Veeravalli, Vijayabhaskar Veeravalli, Lyndah Lovell, Martin Kögler, Hubert Hřebabecký, Eliška Procházková, Ondřej Nešuta, Ondřej Nešuta, Amanda Donoghue, Jenny Lam, Rana Rais, Rana RaisCamilo Rojas, Camilo Rojas, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Radim Nencka

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6028-6056
Number of pages29
JournalJournal of medicinal chemistry
Volume63
Issue number11
DOIs
StatePublished - Jun 11 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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