Agents for the treatment of brain edema. 2. [(2,3,9,9a-Tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids and some of their analogs

Abstract

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.

Astrocytic Swelling Due to Hypotonic or High K+Medium Causes Inhibition of Glutamate and Aspartate Uptake and Increases Their Release

“…We and others have sug gested that swelling-induced release of EAA may be due to the opening of swelling-activated channels, which allows anions as large as glutamate to pass (Kimelberg et al, 1990;Sanchez-Olea et al, 1991;Jalonen, 1993;Roy and Malo, 1993). This transport system is also inhibited by anion transport inhibi tors and seems particularly sensitive to the anion transport inhibitor L-644,711, a compound that we have shown is protective in animal models of isch emia and head injury (Cragoe et al, 1986). Finally the inhibition of the high [K+]o induced release of eH]o-aspartate, but not the hy potonic media-induced release, by a decrease in temperature from 37 to 26°C may be relevant to the well-known protective effect of modestly lowered temperatures (Busto et al, 1987(Busto et al, , 1989Xue et al, 1992) and inhibition of glutamate release (Busto et al, 1989) in ischemia.…”

Treatment of Vasogenic Brain Edema with the Novel Cl− Transport Inhibitor Torasemide

“…This assumption is supported by findings on blocking of anion carriers in red blood cells by such diuretics as furosemide, a structural analog of torasemide (see earlier) (Brazy and Gunn, 1976). Other inhibitors of anion carriers, for example alcanoic acids and their analogs, with limited saluretic properties, were also effective in attenuating brain edema (Cragoe et al, 1986;Kimelberg et al, 1988;Faraj et al, 1988;Staub et al, 1993).…”

Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures

“…In spite of such uncertainties, treatment of excitotoxin-mediated CNS injury with agents such as L644,7 11 might provide a potentially useful additional or alternative therapy to the proposed use of NMDA receptor blockers (Simon et al, 1984;Wieloch, 1985;Choi, 1988). Indeed, we have shown that L644,7 11 and related compounds lead to improved mortality and morbidity in an experimental closed head injury model (Nelson et al, 1982;Cragoe et al, 1986;Kimelberg et al, 1987) and in a tyramine-induced brain edema model in dogs (Faraj et al, 1988). The parent compound ethacrynic acid was also found to be effective in a preliminary clinical trial (Yen et al, 1979).…”