Metabolism of a novel skepinone l-like p38 mitogen-activated protein kinase inhibitor

Abstract

The p38 mitogen-activated protein kinase (MAPK) is a key mediator in cytokine-induced signaling events and is activated in response to a variety of extracellular stimuli such as stress factors, UV-light and inflammatory cytokines. Therefore, the p38 MAP kinase plays an integral role in disease states including oncogenesis, immune disorders and inflammatory processes. Recently a novel class of highly selective p38α inhibitors was described and characterized as tools and probes for in vivo studies. The objective of the current study was the preclinical characterization of 3-((2,4-difluorophenyl)amino)dibenzo[b,e]oxepin-11(6H)-one, a potent p38α MAP kinase inhibitor. In rat and human hepatic microsomal incubations, the examined compound is completely inactivated (concerning the inhibitory potency of the isolated p38α enzyme) by a CYP2B6 mediated phase 1 metabolism. The dehalogenation and subsequent hydroxylation in the para position of the 2,4-difluorophenyl residue was found to be the predominant transformation. The metabolite was detected in different quantities in both species. In a consecutive reaction the phase 1 metabolite conjugates with glucuronic acid in terms of a phase 2 metabolism. The responsible isoenzymes were identified to be UGT1A3, UGT1A9 and UGT1A10. In this reaction UGT1A10 is the predominant driver of the conversion. Similar to the phase 1 metabolite, the conjugate could also be found in different amounts in both examined species.