Water-Soluble Progesterone Analogues Are Effective, Injectable Treatments in Animal Models of Traumatic Brain Injury
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- 作者：David B. Guthrie ; Donald G. Stein ; Dennis C. Liotta ; Mark A. Lockwood ; Iqbal Sayeed ; Fahim Atif ; Richard F. Arrendale ; G. Prabhakar Reddy ; Taylor J. Evers ; Jose R. Marengo ; Randy B. Howard ; Deborah G. Culver ; Michael G. Natchus
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：May 10, 2012
- 年：2012
- 卷：3
- 期：5
- 页码：362-366
- 全文大小：301K
- 年卷期：v.3,no.5(May 10, 2012)
- ISSN：1948-5875
文摘
After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries. It is currently being investigated in two, independent phase III clinical trials in hospital settings; however, it presents a formidable solubility challenge that has so far prevented the identification of a formulation that would be suitable for emergency field response use or battlefield situations. Accordingly, we have designed and tested a novel series of water-soluble analogues that address this critical need. We report here the synthesis of C-20 oxime conjugates of progesterone as therapeutic agents for traumatic brain injuries with comparable efficacy in animal models of traumatic brain injury and improved solubility and pharmacokinetic profiles. Pharmacodynamic analysis reveals that a nonprogesterone steroidal analogue may be primarily responsible for the observed activity.<br>