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Author Notes:

Author Contributions: The manuscript was written through contributions of D.B.G., D.G.S., M.A.L., M.G.N., and D.C.L. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Subjects:

Research Funding:

The Emory Institute for Drug Discovery, Emory University.

Keywords:

  • Traumatic brain injury
  • traumatic brain injury
  • progesterone
  • neurosteroid
  • progesterone analogues

Water-Soluble ProgesteroneAnalogues Are Effective,Injectable Treatments in Animal Models of Traumatic Brain Injury

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Journal Title:

ACS Medicinal Chemistry Letters

Volume:

Volume 3, Number 5

Publisher:

, Pages 362-366

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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.

Copyright information:

© 2012 American Chemical Society

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