Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7)-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro--pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole -demethylase and terfenadine hydroxylase activity, with values of 0.96 and 2.61 M, respectively. It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a value of 3.61 M. Preincubation of LKY-047 with HLMs and NADPH did not alter inhibition potency, indicating that it is not a mechanism-based inhibitor. LKY-047 was found to be a selective CYP2J2 inhibitor with no inhibitory effect on other human P450s, such as CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A (IC > 50 M). These in vitro data support the use of LKY-047 as a selective CYP2J2 inhibitor with potential application in the identification of P450 isoforms responsible for drug metabolism in reaction phenotyping assays.
Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as attractive therapeutic strategies for the management of severe vascular inflammatory diseases. Recently, we found that JH‐4, a synthesized decursin derivative, exhibited a strong anti‐Hutchinson‐Gilford progeria syndrome by efficiently blocking progerin‐lamin A/C binding. In this study, we examined the effects of JH‐4 on HMGB1‐mediated septic responses and the survival rate in a mouse sepsis model. The anti‐inflammatory activities of JH‐4 were monitored based on its effects on lipopolysaccharide‐ or cecal ligation and puncture (CLP)‐mediated release of HMGB1. The antiseptic activities of JH‐4 were determined by measuring permeability, leukocyte adhesion, migration, and the activation of proinflammatory proteins in HMGB1‐activated human umbilical vein endothelial cells and mice. JH‐4 inhibited the release of HMGB1 and downregulated HMGB1‐dependent inflammatory responses in human endothelial cells. JH‐4 also inhibited HMGB1‐mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with JH‐4 reduced CLP‐induced release of HMGB1, sepsis‐related mortality, and pulmonary injury in vivo. Our results indicate that JH‐4 is a possible therapeutic agent to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.
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