Neurotherapeutic Potential of Water-Soluble pH-Responsive Prodrugs of EIDD-036 in Traumatic Brain Injury

  • J Med Chem. 2023 Apr 27;66(8):5397-5414. doi: 10.1021/acs.jmedchem.2c01484.
Russell G Fritzemeier  1 ,  Aletta E van der Westhuyzen  1 ,  Michael D'Erasmo  1 ,  Savita K Sharma  1 ,  Perry Bartsch  1 ,  Luke E Hodson  1 ,  Ken Liu  1 ,  Bushra Wali  2 ,  Iqbal Sayeed  2 ,  Dennis C Liotta  1
Affiliations
  • 1. Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
  • 2. Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
PMID: 37026870 DOI: 10.1021/acs.jmedchem.2c01484
Abstract

The C-20 oxime of progesterone, EIDD-036 (2), demonstrates neuroprotection and improved outcomes in animal models of traumatic brain injury (TBI). However, 2 suffers from poor solubility, which renders it unsuitable for rapid administration. Previous prodrugs of 2 aimed at improving solubility by incorporating enzymatically labile amino acid and phosphate ester promoieties. These approaches were effective but led to limitations with in vivo administration. Herein, we disclose a pH-responsive water-soluble prodrug strategy to improve exposure to 2 through enzyme-independent activation. Compound 13l was identified as a lead that exhibits water-solubility, stability in acidic solutions, and rapid conversion to 2 at physiological pH. Administration of 13l to rats resulted in a twofold increase in exposure to 2 compared to the previous generation phosphate prodrug, EIDD-1723 (6). In a rat model of TBI, treatment with 13l resulted in a significant decrease in cerebral edema when administered postinjury.

Products