前药
化学
溶解度
体内
药理学
神经保护
创伤性脑损伤
磷酸盐
生物化学
医学
有机化学
生物技术
精神科
生物
作者
Russell G. Fritzemeier,Aletta E. van der Westhuyzen,Michael P. D’Erasmo,Savita K. Sharma,Perry W. Bartsch,Luke E. Hodson,Ken Liu,Bushra Wali,Iqbal Sayeed,Dennis C. Liotta
标识
DOI:10.1021/acs.jmedchem.2c01484
摘要
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.
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