Abstract
Two representative compounds from a novel chemical series of potent inhibitors of lipid peroxidation are described. The compounds 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)-triene-3,20-dione monomethane sulfonate (U74006F) and 21-[4-(3,6-bis(diethylamino)-2-pyridinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)triene-3,20-dione hydrochloride (U74500A) inhibited lipid peroxidation in brain homogenates and purified brain synaptosomes under a variety of conditions involving iron. With IC50 values ranging from 2 to 60 microM, U74006F and U74500A were comparable in potency to alpha-tocopherol or butylated hydroxytoluene and were nearly 100 times as potent as desferrioxamine. Some specificity for intact phospholipid membranes is suggested since the ability of U74006F or U74500A to inhibit lipid peroxidation was greatly reduced in methanol solutions of arachidonic acid. Despite close similarities in their structures, their response to increasing concentrations of Fe2+ in lipid peroxidation assays differed qualitatively. One of the compounds, U74500A, may act as a membrane localized chelator of iron.
Highlights
In in uivo models of experimental central nervous system traumaand i~chemia."~Thisreport describes the i n vitro activity of two compounds of the chemical series, U74006F4 and U74500A (Fig. 1).One of these, U74006F, is being developed for clinical trials in the treatment of head and spinal cord injuries and stroke
The compounds 21-[4-(2,6-di-I-pyrrolidi-by the formation of thiobarbituric acid reactive products (TBAR) as nyl-4-pyrimidiny1)-1-piperazinyll- 16a-methylpregna- described [11]
Despite close similarities in their structures, their response to increasing concentrations of Fez+ inlipid peroxidation assays difin the presence of 20% ethanol which eliminated glass binding during the assay
Summary
In in uivo models of experimental central nervous system traumaand i~chemia."~Thisreport describes the i n vitro activity of two compounds of the chemical series, U74006F4 and U74500A (Fig. 1).One of these, U74006F, is being developed for clinical trials in the treatment of head and spinal cord injuries and stroke. In some cases, purified rat brain synaptosomes were prepared as described [18] with modification [11]and were used immecal seriesof potent inhibitors of lipid peroxidation are diately. S. ene-3,aO-dione hydrochloride (U74500A) inhibited patent application 4236 and European patent application 4236.P. lipid peroxidation in brain homogenates and purified brain synaptosomes under a variety of conditions involving iron.
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