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Adenosine Kinase Inhibitors. 2. Synthesis, Enzyme Inhibition, and Antiseizure Activity of Diaryltubercidin Analogues

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    Adenosine Kinase Inhibitors. 2. Synthesis, Enzyme Inhibition, and Antiseizure Activity of Diaryltubercidin Analogues
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2000, 43, 15, 2894–2905
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    https://doi.org/10.1021/jm0000259
    Published July 7, 2000
    Copyright © 2000 American Chemical Society
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    In the preceding article (Ugarkar et al. J. Med. Chem.2000, 43) we reported that analogues of tubercidin are potent adenosine kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model. Despite the discovery of several highly potent AK inhibitors (AKIs), e.g., 5‘-amino-5‘-deoxy- 5-iodotubercidin (1c) (IC50 = 0.0006 μM), no compounds were identified that exhibited a safety, efficacy, and side effect profile suitable for further development. In this article, we demonstrate that substitution of the tubercidin molecule with aromatic rings at the N4- and the C5-positions not only retains AKI potency but also improves in vivo activity. Synthesis of such compounds entailed transformation of 4-arylamino-5-iodotubercidin analogues to their corresponding 5-aryl derivatives via the Suzuki reaction. Alternatively, 4-N-arylamino-5-arylpyrrolo[2,3-d]pyrimidine bases were constructed and then glycosylated with appropriately protected α-ribofuranosyl chlorides using a phase-transfer catalyst. Several compounds exhibited potent activity in the rat MES seizure assay with ED50s ≤ 2.0 mg/kg, ip, and showed relatively mild side effects.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2000, 43, 15, 2894–2905
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm0000259
    Published July 7, 2000
    Copyright © 2000 American Chemical Society
    Request reuse permissions

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