Department of Neurology, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
J Med Chem. 2022 Aug 25;65(16):11111-11125. doi: 10.1021/acs.jmedchem.2c00562. Epub 2022 Aug 5.
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-imethoxy-4-(5-henyl-4-hiophen-2-yl-1-midazol-2-yl)henol (DPTIP) is one of the most potent (IC = 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 () with a 2',6'-diethyl-1,4'-bipiperidinyl promoiety exhibited >fourfold higher plasma (AUC = 1047 pmol·h/mL) and brain exposures (AUC = 247 pmol·h/g) DPTIP and a significant enhancement of DPTIP half-life (2 h ∼0.5 h). In a mouse model of acute brain injury, DPTIP released from 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.
细胞外囊泡 (EVs) 可以携带病理 cargo，并在疾病进展中发挥积极作用。中性鞘磷脂酶-2 (nSMase2) 是 EV 生物发生的关键调节因子，其抑制在多种疾病状态下显示出保护作用。2,6-二甲氧基-4-(5-苯基-4-噻吩-2-基-1-咪唑-2-基)苯酚 (DPTIP) 是迄今为止发现的最有效的 nSMase2 抑制剂之一 (IC = 30 nM)。然而，DPTIP 表现出较差的口服药代动力学 (PK)，限制了其临床开发。为了克服 DPTIP 的 PK 限制，我们通过掩蔽其酚羟基合成了一系列前药。当口服给予时，带有 2'，6'-二乙基-1,4'-联哌啶基促进基团的最佳前药 () 表现出 >4 倍更高的血浆 (AUC = 1047 pmol·h/mL) 和脑暴露 (AUC = 247 pmol·h/g)，比 DPTIP 和显著提高了 DPTIP 的半衰期 (2 h ∼0.5 h)。在急性脑损伤的小鼠模型中，从 释放的 DPTIP 显著抑制了 IL-1β 诱导的 EV 向血浆中的释放，并减弱了 nSMase2 活性。这些研究报告了发现一种具有临床转化潜力的 DPTIP 前药。
