Agents for the treatment of brain edema. 2. [(2,3,9,9a-Tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]+ ++alkanoi c acids and some of their analogues.
Our initial paper discussed brain edema resulting from traumatic head injury and the need for specific and effective agents to treat the disorder and disclosed a novel approach for the discovery of a drug of this kind. The current study describes the synthesis of a series of [(2,3,9,9a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alk anoic acids and their analogues. These compounds were evaluated in an in vitro cerebrocortical tissue slice assay for their relative potencies in inhibiting K+ + HCO3- induced swelling. Structural modification at a number of sites in the "lead" compound revealed that significant biological activity was inherent only within a very narrow range of structural types. The observation that nearly all the biological activity resided in one of the two enantiomers demonstrated the marked stereospecificity of the most active compounds. One of the most potent compounds, (R)-(+)-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren -7-yl) oxy]acetic acid ((+)-5c), exhibited a dose-response relationship in the in vivo acceleration/deceleration brain edema assay, and the data from the two highest doses were statistically significant. Electron microscopic examination demonstrated that the perivascular astroglial swelling that arises from this procedure is abolished in the animals treated with (+)-5c. This compound is currently being evaluated for its clinical efficacy and safety in the treatment of traumatic head injury.
E J
EJ
Cragoe
O W
OW
Woltersdorf
N P
NP
Gould
A M
AM
Pietruszkiewicz
C
C
Ziegler
Y
Y
Sakurai
G E
GE
Stokker
P S
PS
Anderson
R S
RS
Bourke
H K
HK
Kimelberg
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy*; D002415:Cats; D002712:Chlorides / Q000378:metabolism; D006259:Craniocerebral Trauma / Q000150:complications; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D009457:Neuroglia / Q000648:ultrastructure; D051381:Rats; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D002712:Chlorides