title: Water-soluble progesterone analogues are effective, injectable treatments in animal models of traumatic brain injury.
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.
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Guthrie
authors.affiliation: Emory University School of Medicine, Department of Emergency Medicine, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States ; Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lockwood
authors.affiliation: Emory University School of Medicine, Department of Emergency Medicine, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
authors.affiliation: Emory University School of Medicine, Department of Emergency Medicine, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Fahim
authors.initials: F
authors.lastname: Atif
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Arrendale
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: G Prabhakar
authors.initials: GP
authors.lastname: Reddy
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Evers
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Marengo
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Randy B
authors.initials: RB
authors.lastname: Howard
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Culver
authors.affiliation: Emory Institute for Drug Discovery (EIDD), Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Natchus
keywords: Traumatic brain injury; neurosteroid; progesterone; progesterone analogues; traumatic brain injury