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dc.contributor.authorBlake, Linda Cherise
dc.contributor.authorRoy, Anuradha
dc.contributor.authorNeul, David
dc.contributor.authorSchoenen, Frank J.
dc.contributor.authorAubé, Jeffrey
dc.contributor.authorScott, Emily E.
dc.date.accessioned2017-06-27T20:46:39Z
dc.date.available2017-06-27T20:46:39Z
dc.date.issued2013-09
dc.identifier.citationBlake, 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-zen_US
dc.identifier.urihttp://hdl.handle.net/1808/24672
dc.descriptionThe original publication is available at www.springerlink.comen_US
dc.description.abstractPURPOSE 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.en_US
dc.publisherSpringer Verlagen_US
dc.subjectCytochrome P450 2A13en_US
dc.subjectCytochrome P450 2A6,Tobaccoen_US
dc.subjectLung canceren_US
dc.subjectChemopreventativeen_US
dc.titleBenzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Usersen_US
dc.typeArticleen_US
kusw.kuauthorBlake, Linda C.
kusw.kuauthorRoy, Anuradha
kusw.kuauthorSchoenen, Frank J.
kusw.kuauthorAubé, Jeffrey
kusw.kuauthorScott, Emily E.
kusw.kudepartmentMedicinal Chemistryen_US
dc.identifier.doi10.1007/s11095-013-1054-zen_US
dc.identifier.orcidhttps://orcid.org/0000-0003-1049-5767
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC3781598en_US
dc.rights.accessrightsopenAccess


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