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    Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users

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    Scott_2013.pdf (1.050Mb)
    Issue Date
    2013-09
    Author
    Blake, Linda Cherise
    Roy, Anuradha
    Neul, David
    Schoenen, Frank J.
    Aubé, Jeffrey
    Scott, Emily E.
    Publisher
    Springer Verlag
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
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    Abstract
    PURPOSE 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. METHODS Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is the major challenge in compound design. RESULTS A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. CONCLUSIONS Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure.
    Description
    The original publication is available at www.springerlink.com
    URI
    http://hdl.handle.net/1808/24672
    DOI
    https://doi.org/10.1007/s11095-013-1054-z
    Collections
    • Medicinal Chemistry Scholarly Works [225]
    Citation
    Blake, L. C., Roy, A., Neul, D., Schoenen, F. J., Aubé, J., & Scott, E. E. (2013). Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users. Pharmaceutical Research, 30(9), 2290–2302. http://doi.org/10.1007/s11095-013-1054-z

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    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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