Biol. Pharm. Bull. 29(6) 1282—1285 (2006)

among the most widely prescribed drugs worldwide for the treatment of inflammation, pain, and fever. However, the use of those drugs is often limited by numerous side effects, particularly in the gastrointestinal tract and the kidney. The inflammatory action of NSAIDs is attributed to the inhibition of cyclooxygenase (COX), and consequently, the conversion of arachidonic acid into prostaglandins (PGs). It is hypothesized that the undesirable side effects of NSAIDs are associated with the inhibition of COX-1 (constitutive isoform), whereas the beneficial effects are related to the inhibition of COX-2 (inducible isoform). While COX-2 selective inhibitors seem to be safer than non-selective NSAID with regard to gastrointestinal damage, they decrease vascular prostacyclin (PGI2) production and may affect the balance between pro-thrombotic and anti-thrombotic eicosanoids. The decrease of vasodilatory and anti-aggregatory PGI2 production may tip the balance in favor of pro-thrombotic eicosanoids such as thromboxane A2 and may cause increase of cardiovascular thrombotic events. Due to these possibly serious cardiovascular side effects, the manufacturer of rofecoxib, the first COX-2 selective NSAID, decided to voluntarily withdraw the drug from the market in 2004, and other drugs in the same category are under close review thereafter. This event brought significant impact on clinicians and patients, and many of them are seeking for alternative medication. Therefore, NSAID which exhibits less gastrointestinal and cardiovascular side effects have earned a major interest from many medicinal chemists as a new option for the management of diseases that requires long-term use of the anti-inflammatory medications. Compounds that simultaneously inhibit cyclooxygenase and 5-lipoxygenase (5-LOX) have received attention from medicinal chemists because inhibition of 5-LOX blocks the production of LTB4, a leucotriene, which plays an important role in the development of gastrointestinal ulcers. Recently, we have synthesized 17 compounds which had dual inhibition of COX and 5-LOX. Among the 17 prepared compounds, 1-furan-2-yl-3-pyridine-2-yl-propenone (FPP-3) demonstrated the most significant dual COX/5-LOX inhibitory activity. Chemical structure of FPP-3 is shown in Fig. 1. We further investigated the effect of the compound on other pro-inflammatory cytokines and demonstrated that FPP-3 decreased expression of nitric oxide synthase and production of tumor necrosis factor-a in vitro. In this study, we examined the effects of the propenone compound, FPP-3, on the pharmacokinetics of theophylline, a commonly prescribed medication for the patients with asthma or chronic obstructive pulmonary disease. We also studied cytochrome P450 activity test to investigate drug interaction of FPP-3 with theophylline because CYP 1A is a predominant enzyme for the metabolism of the latter.