Mechanism‐Based Inhibition of Human Cytochrome P450 2D6 by Schering 66712

Abstract

Schering 66712 (5‐fluoro‐2‐[4‐[(2‐phenyl‐1H‐imidazol5‐yl)methyl]‐1‐piperzainyl]pyrimidine) is a mechanism‐based inactivator of human cytochrome P450 2D6 (P450 2D6) that displays Type I binding with KS of 0.39 ± 0.10 μM. The partition ratio is approximately 300. Inactivation was not prevented by addition of an exogenous nucleophiles including potassium cyanide. Within 15 minutes of incubation with Schering 66712 and NADPH, ~100% of P450 2D6 activity was lost with ~40% loss in ability to binding CO. These findings support inactivation primarily by adduction of protein. ESI‐LC‐MS analysis of whole protein also indicates the presence of a protein adduct. Modeling of Schering 66712 in the active site of P450 2D6 suggests interaction between the phenyl group of Schering 66712 and the heme iron. (Supported by: NIH GM086767‐01 and RGM086767Z, a grant from the Howard Hughes Medical Institute to Kalamazoo College, and the Hutchcroft Fund of Kalamazoo College).