Molecular characterization of EP6-A novel imidazo[1,2-a]pyridine based direct 5-lipoxygenase inhibitor

作者：Wisniewska Joanna M; Roedl Carmen B; Kahnt Astrid S; Buscato Estella; Ulrich Sandra; Tanrikulu Yusuf; Achenbach Janosch; Roersch Florian; Groesch Sabine; Schneider Gi**ert; Cinatl Jindrich Jr; Proschak Ewgenij; Steinhilber Dieter; Hofmann Bettina^*

来源：Biochemical Pharmacology, 2012, 83(2): 228-240.

DOI：10.1016/j.bcp.2011.10.012

• 5-Lipoxygenase
• Inflammation
• Inhibitor
• Leukotrienes
• Molecular modeling

5-Lipoxygenase (5-LO) is a crucial enzyme of the arachidonic acid (AA) cascade and catalyzes the formation of bioactive leukotrienes (LTs) which are involved in inflammatory diseases and allergic reactions. The pathophysiological effects of LTs are considered to be prevented by 5-LO inhibitors. In this study we present cyclohexyl-[6-methyl-2-(4-morpholin-4-yl-phenyl)-imidazon,2-cdpyridin-3-yl]amine (EP6), a novel imidazo[1,2-a]pyridine based compound and its characterization in several in vitro assays. Ep6 suppresses 5-LO activity in intact polymorphonuclear leukocytes with an IC(50) value of 0.16 mu M and exhibits full inhibitory potency in cell free assays (IC(50) value of 0.05 mu M for purified 5-LO). The efficacy of EP6 was not affected by the redox tone or the concentration of exogenous AA, characteristic drawbacks known for the class of nonredox-type 5-LO inhibitors. Furthermore, EP6 suppressed 5-LO activity independently of the cell stimulus or the activation pathway of 5-LO contrary to what is known for some nonredox-type inhibitors. Using molecular modeling and site-directed mutagenesis studies, we were able to derive a feasible binding region within the C2-like domain of 5-LO that can serve as a new starting point for optimization and development of new 5-LO inhibitors targeting this site. EP6 has promising effects on cell viability of tumor cells without mutagenic activity. Hence the drug may possess potential for intervention with inflammatory and allergic diseases and certain types of cancer including leukemia.

• 出版日期2012-1-15
• 单位河北医科大学