Design and Synthesis of Selective, High-Affinity Inhibitors of Human Cytochrome P450 2J2.

Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Universite Paris 5 René Descartes, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 06/2006; 16(10):2777-80. DOI: 10.1016/j.bmcl.2006.02.004
Source: PubMed

ABSTRACT The active site topology, substrate specificity, and biological roles of the human cytochrome P450 CYP2J2, which is mainly expressed in the cardiovascular system, are poorly known even though recent data suggest that it could be a novel biomarker and potential target for therapy of human cancer. This paper reports a first series of high-affinity, selective CYP2J2 inhibitors that are related to terfenadine, with K(i) values as low as 160nM, that should be useful tools to determine the biological roles of CYP2J2.

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    ABSTRACT: Cytochrome P450 2J2 (CYP2J2) is an enzyme mainly found in human extrahepatic tissues, with predominant expression in the cardiovascular system. CYP2J2 plays important roles in the metabolism of endogenous metabolites and therapeutic drugs, such as arachidonic acid, astemizole, ebastine, and terfenadine. CYP2J2 is also overexpressed in human cancer tissues and cancer cell lines and may represent a potential target for therapy of human cancers. In this study, 10 natural products obtained from plants and microorganisms were screened as potential CYP2J2 inhibitors. Among them, thelephoric acid showed strong inhibition of astemizole O-demethylation activity () in a dose-dependent manner. Evaluation of the substrate dependency of the inhibitory activity of thelephoric acid showed that it strongly inhibited CYP2J2-mediated ebastine hydroxylation () and terfenadine hydroxylation () in a substrate nondependent manner. The present data suggest that this compound might be a potential candidate for further evaluation for anticancer activity.
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