Small Molecule Neutral Sphingomyelinase 2 (nSMase2) Inhibitors

Unmet Need
Neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and hydrolyzes sphingomyelin, producing the lipid ceramide, which functions in stress responses leading to apoptosis, cell growth arrest, and differentiation.  Increased levels of ceramides have been associated with many neurological disorders, including Alzheimer’s disease, multiple sclerosis, HIV-associated neurocognitive disorders, Parkinson’s disease, and ALS.  Although nSMase2 remains an attractive target for therapeutics for these diseases, currently available nSMase2 inhibitors are metabolically unstable and exhibit low potency in vivo.
 
Technology Overview
Researchers at Johns Hopkins have developed novel small molecules that strongly inhibit nSMase2. First, the researchers identified key moieties required for nSMase2 inhibition by 2,6-dimethoxy-4-[4-phenyl-5-(2-thienyl)-1H-imidazol-2-yl] phenol (DPTIP). The inventors then synthesized molecular derivatives that varied at these key moieties and evaluated their potency as nSMase2 inhibitors.
 
Stage of Development
The invention is in the discovery phase. Inventors have synthesized novel small molecule nSMase2 inhibitors, and evaluated the in vitro inhibitory potencies of these compounds using human nSMase2 assays. Selected compounds underwent in vitro metabolic stability studies in mouse and human liver microsomes before being used in in vivo pharmacokinetics studies in a mouse model.
 
Publications
Stepanek, et al. EJMECH 2019
 

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