Pharmaceutics, Год журнала: 2024, Номер 17(1), С. 20 - 20

Опубликована: Дек. 26, 2024

Background: Extracellular vesicles (EVs) can carry pathological cargo, contributing to disease progression. The enzyme neutral sphingomyelinase 2 (nSMase2) plays a critical role in EV biogenesis, making it promising therapeutic target. Our lab previously identified potent and selective inhibitor of nSMase2, named DPTIP (IC50 = 30 nM). Although promising, exhibits poor pharmacokinetics (PKs) with low oral bioavailability (%F < 5), short half-life (t1/2 ≤ 0.5 h). To address these limitations, we developed prodrugs by masking its phenolic hydroxyl group, demonstrating improved plasma exposure mice. Recognizing that species-specific metabolic differences influence prodrug PK, expanded our studies evaluate selected both mice dogs. Methods: scaleup was completed two additional valine- ester based were synthesized. Mice dosed via peroral route (10 mg/kg equivalent). For dog intravenous (1 mg/kg) or (2 given at dose equivalent. Plasma samples collected predetermined points analyzed using LC/MS-MS methods. Results: In mice, several the tested showed similar exposures compared DPTIP. However, studies, double valine 9, significant improvement an almost two-fold increase (AUC0-t 1352 vs. 701 pmol·h/mL), enhancing from 8.9% 17.3%. Conclusions: These findings identify 9 as candidate for further evaluation underscore PKs.

Язык: Английский