A novel 1,5-diarylpyrazole derivative exerts its anti-inflammatory effect by inhibition of cyclooxygenase-2 activity as a prodrug

Abstract

In the present study, we designed and synthesized a novel 1,5-diarylpyrazole derivative, 2-amino-N-(2-methyl-5-(1-(4-sulfamoylphenyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)phenyl) acetamide hydrochloride (CC06), which was intended to act as a prodrug and would exert potent anti-inflammatory activity after being converted to its parent compound in vivo. In vitro cell-based biological assay, CC06 showed decreased inhibitory effects on cyclooxygenase (COX)-1 and COX-2 compared with its parent compounds, but it exhibited potent anti-inflammatory activity in vivo. The anti-inflammatory effect was evaluated in a carrageenan-induced rat paw edema model and CC06 (15, 30, 60 mg/kg, intragastrically) reduced rat paw edema in a dose-dependent manner. CC06 is also a selective inhibitor of COX-2 since it can reduce prostaglandin E2 (PGE2) production in the inflamed pouch dose-dependently without affecting PGE2 production in stomach in rat air pouch model. Furthermore, preliminary pharmacokinetics experiments were conducted using high performance liquid chromatography/mass spectrometry (HPLC/MS) to detect whether CC06 can convert to its parent compound or not. Our results supported the hypothesis that CC06 was actually converted to its parent compound. These suggested that CC06 served as an anti-inflammatory prodrug and actually converted to its parent compound to exert its anti-inflammatory effect. This finding will be of great benefit in carrying out structural modifications of prodrug-like selective COX-2 inhibitors. © 2009 Pharmaceutical Society of Japan.