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OtherNEUROPHARMACOLOGY

Pyrrolopyrimidines: Novel Brain-Penetrating Antioxidants with Neuroprotective Activity in Brain Injury and Ischemia Models

E. D. Hall, P. K. Andrus, S. L. Smith, T. J. Fleck, H. M. Scherch, B. S. Lutzke, G. A. Sawada, J. S. Althaus, P. F. Vonvoigtlander, G. E. Padbury, P.G. Larson, J. R. Palmer and G. L. Bundy
Journal of Pharmacology and Experimental Therapeutics May 1997, 281 (2) 895-904;
E. D. Hall
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P. K. Andrus
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S. L. Smith
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T. J. Fleck
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H. M. Scherch
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B. S. Lutzke
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G. A. Sawada
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J. S. Althaus
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P. F. Vonvoigtlander
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G. E. Padbury
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P.G. Larson
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J. R. Palmer
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G. L. Bundy
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Abstract

A novel group of antioxidant compounds, the pyrrolopyrimidines, has been discovered recently. Many of these possess significantly improved oral bioavailability (56–70% in rats), increased efficacy and potency in protecting cultured neurons against iron-induced lipid peroxidative injury and as much as a 5-fold increase in brain uptake compared with the 21-aminosteroid antioxidant compound, tirilazad mesylate (U-74006F), described earlier. They appear to quench lipid peroxidation reactions by electron-donating and/or radical-trapping mechanisms. Several compounds in the series, such as U-101033E and U-104067F, demonstrate greater ability than tirilazad to protect the hippocampal CA1 region in the gerbil transient (5-min) forebrain ischemia model. Delaying treatment until 4 hr after the ischemic insult still results in significant CA1 neuronal protection. U-101033E is still effective in salvaging a portion of the CA1 neuronal population when the ischemic duration is extended to 10 min. In addition, U-101033E has been found to be protective in the context of focal cerebral ischemia, reducing infarct size in the mouse permanent middle cerebral artery occlusion model, in contrast to tirilazad which is minimally effective. These results suggest that antioxidant compounds with improved brain parenchymal penetration are better able to limit certain types of ischemic brain damage than those which are localized in the cerebral microvasculature. However, the activity of U-101033E in improving early post-traumatic recovery in mice subjected to severe concussive head injury is similar to that of tirilazad. Last, the oral bioavailability of many pyrrolopyrimidines suggests that they may be useful for certain chronic neurodegenerative disorders in which lipid peroxidation plays a role.

Footnotes

  • Send reprint requests to: Edward D. Hall, Ph.D., CNS Diseases Research 7251–209-407, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49001.

  • Abbreviations:
    LP
    lipid peroxidation
    SAH
    subarachnoid hemorrhage
    BBB
    blood-brain barrier
    MCA
    middle cerebral artery
    PBN
    N-tert-butyl-α-phenylnitrone
    HPLC
    high-performance liquid chromatography
    CNS
    central nervous system
    3H-AIB
    [3H]-α(methylamino)isobutyric acid
    • Received September 16, 1996.
    • Accepted January 30, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 2
1 May 1997
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OtherNEUROPHARMACOLOGY

Pyrrolopyrimidines: Novel Brain-Penetrating Antioxidants with Neuroprotective Activity in Brain Injury and Ischemia Models

E. D. Hall, P. K. Andrus, S. L. Smith, T. J. Fleck, H. M. Scherch, B. S. Lutzke, G. A. Sawada, J. S. Althaus, P. F. Vonvoigtlander, G. E. Padbury, P.G. Larson, J. R. Palmer and G. L. Bundy
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 895-904;

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OtherNEUROPHARMACOLOGY

Pyrrolopyrimidines: Novel Brain-Penetrating Antioxidants with Neuroprotective Activity in Brain Injury and Ischemia Models

E. D. Hall, P. K. Andrus, S. L. Smith, T. J. Fleck, H. M. Scherch, B. S. Lutzke, G. A. Sawada, J. S. Althaus, P. F. Vonvoigtlander, G. E. Padbury, P.G. Larson, J. R. Palmer and G. L. Bundy
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 895-904;
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