Development of neutral sphingomyelinase 2 (nSMase2) inhibitors for the treatment of Alzheimer's disease

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PROJECT SUMMARY Neutral sphingomyelinase 2 (nSMase2 encoded by SMPD3 gene) is a membrane associated enzyme that catalyzes the hydrolysis of sphingomyelin (SM) into phosphorylcholine and ceramide. Formation of ceramide- enriched areas by the action of nSMase2 is known to facilitate generation of extracellular vesicles, which participate in intercellular communication in both physiological and pathological processes through encapsulation and transfer of diverse types of substances including tau protein. Interestingly, post-mortem brains from AD patients exhibit abnormal increases in ceramide. Inhibition of nSMase2 has therefore become an attractive therapeutic strategy to treat AD by inhibiting EV biogenesis to slow the spread of pathogenic cargo. The main objective of this project is to conduct structural optimization using (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6- dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate (PDDC), a prototype nSMase2 inhibitor, as a molecular template with the ultimate goal of identifying development candidates with balanced overall pharmacological profiles required for clinical translation. By assembling a multidisciplinary team of investigators with complementary expertise, we are poised to seize this opportunity by executing the following specific aims; (Aim 1) Conduct structure-activity relationship (SAR) studies on nSMase2 inhibitors containing a core scaffold different from that of PDDC; (Aim 2) Characterize the ADME (absorption, distribution, metabolism and excretion) and in vitro selectivity/toxicity profile of potent nSMase2 inhibitors from Aim 1. Identify optimal dosing for efficacy studies in Aim 3; (Aim 3) Evaluate selected nSMase2 inhibitors from Aim 2 for efficacy and tolerability in an AAV tau propagation model and a PS19 transgenic model of AD.