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

Abstract：

: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)-imidazo[1,2-a]pyridin-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 0.16μM and exhibits full inhibitory potency in cell free assays (IC(50) value of 0.05μM 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.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Wisniewska JM,Rödl CB,Kahnt AS,Buscató El,Ulrich S,Tanrikulu Y,Achenbach J,Rörsch F,Grösch S,Schneider G,Cinatl J Jr,Proschak E,Steinhilber D,Hofmann B

doi

10.1016/j.bcp.2011.10.012

subject

Has Abstract

pub_date

2012-01-15 00:00:00

pages

228-40

issue

2

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(11)00760-X

journal_volume

83

pub_type

杂志文章

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