Recent pharmacological and genetic evidence in three distinct Alzheimer’s disease (AD) mouse models suggests that the enzyme neutral sphingomyelinase 2 (nSMase2) plays a significant role in tau propagation, a hallmark of AD, and that nSMase2 inhibition could be of use for AD treatment (1, 2). While nSmase2 is emerging as an important player in AD etiology, the current armamentarium of nSMase2 inhibitors is inadequate to develop potential treatments. Currently available inhibitors have many limitations including low potency (IC50’s in µM level), poor solubility, and no brain penetration (3, 4). In collaboration with the National Center for Advancing Translational sciences (NCATS) at NIH, the Institute of Organic Chemistry and Biochemistry (IOCB) from the Czech Republic and Professor Norman Haughey’s laboratory at Johns Hopkins we are conducting a systematic effort to optimize potent, selective, metabolically stable and brain penetrable nSMase2 inhibitors recently identified by high throughput screening to bring to IND enabling studies. NSMase2 is a novel therapeutic target that is mechanistically distinct from previous efforts in AD treatment with the potential of addressing disease progression.
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