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

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.