Design and synthesis of selective, high-affinity inhibitors of human cytochrome P450 2J2

Pierre Lafite; Sylvie Dijols; Didier Buisson; Anne-Christine Macherey; Darryl C Zeldin; Patrick M Dansette; Daniel Mansuy

doi:10.1016/j.bmcl.2006.02.004

Design and synthesis of selective, high-affinity inhibitors of human cytochrome P450 2J2

Bioorg Med Chem Lett. 2006 May 15;16(10):2777-80. doi: 10.1016/j.bmcl.2006.02.004. Epub 2006 Feb 21.

Authors

Pierre Lafite¹, Sylvie Dijols, Didier Buisson, Anne-Christine Macherey, Darryl C Zeldin, Patrick M Dansette, Daniel Mansuy

Affiliation

¹ 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.

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.

MeSH terms

Cytochrome P-450 CYP2J2
Cytochrome P-450 Enzyme Inhibitors*
Cytochrome P-450 Enzyme System / metabolism
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Humans
Magnetic Resonance Spectroscopy
Oxygenases / antagonists & inhibitors*
Oxygenases / metabolism
Substrate Specificity

Substances

CYP2J2 protein, human
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Cytochrome P-450 Enzyme System
Oxygenases
Cytochrome P-450 CYP2J2

Grants and funding

Z99 ES999999/Intramural NIH HHS/United States