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

  • J Med Chem. 2022 Aug 25;65(16):11111-11125. doi: 10.1021/acs.jmedchem.2c00562.
Arindom Pal  1  2 ,  Sadakatali Gori  1  2 ,  Seung-Wan Yoo  1 ,  Ajit G Thomas  2 ,  Ying Wu  2 ,  Jacob Friedman  2 ,  Lukáš Tenora  1  2 ,  Harshit Bhasin  1  2 ,  Jesse Alt  2 ,  Norman Haughey  1  3 ,  Barbara S Slusher  1  2  3  4  5  6  7 ,  Rana Rais  1  2  4
Affiliations
  • 1. Department of Neurology, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
  • 2. Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
  • 3. Departments of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
  • 4. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
  • 5. Department of Oncology, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
  • 6. Departments of Neuroscience, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
  • 7. Department of Medicine, Johns Hopkins School of Medicine, Baltimore Maryland 21205, United States.
PMID: 35930706 DOI: 10.1021/acs.jmedchem.2c00562
Abstract

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.

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