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A pyrroloquinazoline derivative with anti-inflammatory and analgesic activity by dual inhibition of cyclo-oxygenase-2 and 5-lipoxygenase

2002; Elsevier BV; Volume: 434; Issue: 3 Linguagem: Inglês

10.1016/s0014-2999(01)01539-4

1879-0712

Inmaculada Rioja, María Carmen Terencio, Amalia Úbeda, Pedro Molina, Alberto Tárraga, Antonia Gonzalez‐Tejero, María José Alcaraz,

Phenothiazines and Benzothiazines Synthesis and Activities

In a previous study, we reported a new pyrroloquinazoline derivative, 3-(4'-acetoxy-3',5'-dimethoxy)benzylidene-1,2-dihydropyrrolo[2,1-b]quinazoline-9-one (PQ), which inhibited human purified 5-lipoxygenase activity and prostaglandin E2 release in lipopolysaccharide-stimulated RAW 264.7 cells. In the present work, we show that PQ inhibits cyclo-oxygenase-2 activity in intact cell assays (human monocytes) and purified enzyme preparations (ovine isoenzymes) without affecting cyclo-oxygenase-1 activity. This behaviour was confirmed in vivo by using the zymosan-injected mouse air pouch model, where PQ caused a marked reduction in cell migration and leukotriene B4 levels at 4 h, as well as inhibition of prostaglandin E2 levels without affecting cyclo-oxygenase-2 expression at 24 h after zymosan stimulation. In addition, oral administration of this compound significantly reduced carrageenan-induced mouse paw oedema and phenyl-p-benzoquinone-induced writhings in mice. These results indicate that oral PQ exerts analgesic and anti-inflammatory effects, which are related to dual inhibition of cyclo-oxygenase-2 and 5-lipoxygenase activities.