Development of a Neutral Sphingomyelinase 2 Inhibitor for the Treatment of Alzheimer's Disease

0538203 - ÚOCHB 2021 US eng A - Abstrakt
Hollinger, K. R. - Bell, B. J. - Šála, Michal - Dash, R. P. - Thomas, A. G. - Chaudhuri, A. - Kumar, A. - Lovell, L. - Wu, Y. - Rais, R. - Haughey, N. J. - Nencka, Radim - Rojas, C. - Slusher, B. S.
Development of a Neutral Sphingomyelinase 2 Inhibitor for the Treatment of Alzheimer's Disease.
Neurotherapeutics. Springer. Roč. 17, č. 3 (2020), s. 1313-1314. ISSN 1933-7213. E-ISSN 1878-7479.
[ASENT 2020 Annual Meeting /22./. 02.03.2020-05.03.2020, Bethesda]
Institucionální podpora: RVO:61388963
Klíčová slova: Alzheimer * neutral sphingomyelinase 2 * PDDC
Obor OECD: Organic chemistry

Alzheimer’s disease (AD) is characterized by progressive cognitive impairment with increased amyloid and tau deposition along connectivity pathways. Growing evidence supports that extracellular vesicles (EVs) may serve as putative vectors for this “prion-like” transmission. Pharmacological or genetic inhibition of neutral sphingomyelinase 2 (nSMase2) reduces EV release and improves cognition in AD mouse models. Unfortunately, there are no clinically available nSMase2 inhibitors. Our group conducted a high-throughput screening campaign against human nSMase2 followed by extensive structure-activity relationship studies and identified phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b] pyridazin-8-yl) pyrrolidin-3-yl) carbamate (PDDC) as a lead inhibitor. PDDC was found to be a selective, potent nSMase2 inhibitor (IC50 = 300nM), with excellent oral bioavailability (%F = 88) and brain penetration (AUCbrain/AUCplasma = 0.60) in mice. PDDC was also shown to dose-dependently inhibit EV release in both serum-deprived cells in culture and when administered to mice following brain injury; a closest related inactive analog had no effect. PDDC efficacy was tested in the 5XFAD mouse model of AD. While 5XFAD mice experienced significant impairments in fear memory versus age-matched wild type controls, chronic PDDC dosing completely restored cognitive performance to control levels. PDDC was subsequently incorporated into mouse chow at doses designed to deliver up to 100mg/kg per day. The mouse chow provided sustained brain exposures of PDDC (197 nmol/g*h) which stayed above the IC50 throughout the 24-hour testing period. This dosing regimen is now being evaluated in models of tau propagation in PS19 and 3xTg mice. Preliminary data suggests nSMase2 inhibition with PDDC improves cognition in the 5XFAD AD mouse model and, if confirmed, these findings support PDDC as a novel compound for the treatment of progressive cognitive decline in AD.
Trvalý link: http://hdl.handle.net/11104/0316304