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

Autor:	Pal A; 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., Gori S; 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., Yoo SW; Department of Neurology, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States., Thomas AG; Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States., Wu Y; Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States., Friedman J; Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States., Tenora L; 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., Bhasin H; 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., Alt J; Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States., Haughey N; Department of Neurology, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.; Departments of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States., Slusher BS; 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.; Departments of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.; Department of Oncology, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.; Departments of Neuroscience, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.; Department of Medicine, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States., Rais R; 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.; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Aug 25; Vol. 65 (16), pp. 11111-11125. Date of Electronic Publication: 2022 Aug 05.
DOI:	10.1021/acs.jmedchem.2c00562
Abstrakt:	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- D imethoxy-4-(5- p henyl-4- t hiophen-2-yl-1 H - i midazol-2-yl) p henol (DPTIP) is one of the most potent (IC 50 = 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 (AUC 0- t = 1047 pmol·h/mL) and brain exposures (AUC 0- 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.
Databáze:	MEDLINE
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