RESUMEN
The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitor KM55 was rationally designed and synthesized. KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of KM55 in human whole blood and endothelial cells was investigated. KM55 potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. KM55 was also tested in a cell function-based assay. The compound significantly inhibited the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation.
Asunto(s)
Antiinflamatorios/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Ácido Araquidónico/metabolismo , Epóxido Hidrolasas/antagonistas & inhibidores , Hidrocarburos Fluorados/farmacología , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/farmacología , Urea/análogos & derivados , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/química , Inflamación/tratamiento farmacológico , Leucocitos/metabolismo , Leucotrienos/biosíntesis , Lipopolisacáridos , Inhibidores de la Lipooxigenasa/química , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
Modulators of the arachidonic acid cascade have been in the focus of research for treatments of inflammation and pain for several decades. Targeting this complex pathway experiences a paradigm change towards the design and development of multi-target inhibitors, exhibiting improved efficacy and less undesired side effects. This minireview summarizes recent developments in the field of designed multi-target ligands of the arachidonic acid cascade. In addition to the well-known dual inhibitors of 5-lipoxygenase and cyclooxygenase-2 such as licofelone, very recent developments are discussed. Especially, multi-target inhibitors interfering with the cytochrome P450 pathway via inhibition of soluble epoxide hydrolase seem to offer a novel opportunity for development of novel anti-inflammatory drugs.
Asunto(s)
Ácido Araquidónico/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Antiinflamatorios/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirroles/farmacologíaRESUMEN
Current research leads to the assumption that drugs affecting more than one target could result in a more efficient treatment of diseases and fewer safety concerns. Administration of drugs inhibiting only one branch of the arachidonic acid cascade is usually accompanied by side effects. We therefore designed and synthesized a library of hybrid molecules incorporating an imidazo[1,2-a]pyridine and an urea moiety as novel soluble epoxide hydrolase (sEH)/5-lipoxygenase (5-LO) dual inhibitors. Evaluation of the compounds was accomplished by in vitro testing using recombinant enzyme assays.