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 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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