Discovery of Orally Bioavailable and Brain-Penetrable Prodrugs of the Potent nSMase2 Inhibitor DPTIP

Extracellular vesicles (EVs) can carry pathological cargo
and play
an active role in disease progression. Neutral sphingomyelinase-2
(nSMase2) is a critical regulator of EV biogenesis, and its inhibition
has shown protective effects in multiple disease states. 2,6-Dimethoxy-4-(5-phenyl-4-thiophen-2-yl-1H-imidazol-2-yl)phenol (DPTIP) is one of the
most potent (IC50 = 30 nM) inhibitors of nSMase2 discovered
to date. However, DPTIP exhibits poor oral pharmacokinetics (PK),
limiting its clinical development. To overcome DPTIP’s PK limitations,
we synthesized a series of prodrugs by masking its phenolic hydroxyl
group. When administered orally, the best prodrug (P18) with a 2′,6′-diethyl-1,4′-bipiperidinyl promoiety
exhibited >fourfold higher plasma (AUC0–t = 1047 pmol·h/mL) and brain exposures (AUC0–t = 247 pmol·h/g) versus DPTIP
and a significant enhancement of DPTIP half-life (2 h vs ∼0.5 h). In a mouse model of acute brain injury, DPTIP released
from P18 significantly inhibited IL-1β-induced
EV release into plasma and attenuated nSMase2 activity. These studies
report the discovery of a DPTIP prodrug with potential for clinical
translation.