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    Design, synthesis, and evaluation of novel prodrugs of transition state inhibitors of norovirus 3CL protease

    Date
    2017-07-03
    Author
    Kankanamalage, Anushka C. Galasiti
    Kim, Yunjeong
    Rathnayake, Athri D.
    Alliston, Kevin R.
    Butler, Michelle M.
    Cardinale, Steven C.
    Bowlin, Terry L.
    Groutas, William C.
    Chang, Kyeong-Ok
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    Citation
    Anushka C. Galasiti Kankanamalage, Yunjeong Kim, Athri D. Rathnayake, Kevin R. Alliston, Michelle M. Butler, Steven C. Cardinale, Terry L. Bowlin, William C. Groutas, and Kyeong-Ok Chang. Design, Synthesis, and Evaluation of Novel Prodrugs of Transition State Inhibitors of Norovirus 3CL Protease. Journal of Medicinal Chemistry 2017, vol. 60::no. 14:pp 6239-6248
    Abstract
    Ester and carbamate prodrugs of aldehyde bisulfite adduct inhibitors were synthesized in order to improve their pharmacokinetic and pharmacodynamic properties. The inhibitory activity of the compounds against norovirus 3C-like protease in enzyme and cell-based assays was determined. The ester and carbamate prodrugs displayed equivalent potency to those of the precursor aldehyde bisulfite adducts and precursor aldehydes. Furthermore, the rate of ester cleavage was found to be dependent on alkyl chain length. The generated prodrugs exhibited low cytotoxicity and satisfactory liver microsomes stability and plasma protein binding. The methodology described herein has wide applicability and can be extended to the bisulfite adducts of common warheads employed in:the design of transition state inhibitors of serine and cysteine proteases of medical relevance.
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    URI
    http://dx.doi.org/10.1021/acs.jmedchem.7b00497
    http://hdl.handle.net/10057/14054
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