Article date: July 2004
By: Lutz Fischer, Dieter Steinhilber, Oliver Werz in Volume 142, Issue 5, pages 861-868
5‐Lipoxygenase (5‐LO) is a crucial enzyme in the synthesis of the bioactive leukotrienes (LTs) from arachidonic acid (AA), and inhibitors of 5‐LO are thought to prevent the untowarded pathophysiological effects of LTs.
In this study, we present the molecular pharmacological profile of the novel nonredox‐type 5‐LO inhibitor CJ‐13,610 that was evaluated in various in vitro assays.
In intact human polymorphonuclear leukocytes (PMNL), challenged with the Ca2+‐ionophore A23187, CJ‐13,610 potently suppressed 5‐LO product formation with an IC50=0.07 μM. Supplementation of exogenous AA impaired the efficacy of CJ‐13,610, implying a competitive mode of action.
In analogy to ZM230487 and L‐739.010, two closely related nonredox‐type 5‐LO inhibitors, CJ‐13,610 up to 30 μM failed to inhibit 5‐LO in cell‐free assay systems under nonreducing conditions, but inclusion of peroxidase activity restored the efficacy of CJ‐13,610 (IC50=0.3 μM).
In contrast to ZM230487 and L‐739.010, the potency of CJ‐13,610 does not depend on the cell stimulus or the activation pathway of 5‐LO. Thus, 5‐LO product formation in PMNL induced by phosphorylation events was equally suppressed by CJ‐13,610 as compared to Ca2+‐mediated 5‐LO activation. In transfected HeLa cells, CJ‐13,610 only slightly discriminated between phosphorylatable wild‐type 5‐LO and a 5‐LO mutant that lacks phosphorylation sites.
In summary, CJ‐13,610 may possess considerable potential as a potent orally active nonredox‐type 5‐LO inhibitor that lacks certain disadvantages of former representatives of this class of 5‐LO inhibitors.
5‐Lipoxygenase (5‐LO) is a crucial enzyme in the synthesis of the bioactive leukotrienes (LTs) from arachidonic acid (AA), and inhibitors of 5‐LO are thought to prevent the untowarded pathophysiological effects of LTs.
In this study, we present the molecular pharmacological profile of the novel nonredox‐type 5‐LO inhibitor CJ‐13,610 that was evaluated in various in vitro assays.
In intact human polymorphonuclear leukocytes (PMNL), challenged with the Ca2+‐ionophore A23187, CJ‐13,610 potently suppressed 5‐LO product formation with an IC50=0.07 μM. Supplementation of exogenous AA impaired the efficacy of CJ‐13,610, implying a competitive mode of action.
In analogy to ZM230487 and L‐739.010, two closely related nonredox‐type 5‐LO inhibitors, CJ‐13,610 up to 30 μM failed to inhibit 5‐LO in cell‐free assay systems under nonreducing conditions, but inclusion of peroxidase activity restored the efficacy of CJ‐13,610 (IC50=0.3 μM).
In contrast to ZM230487 and L‐739.010, the potency of CJ‐13,610 does not depend on the cell stimulus or the activation pathway of 5‐LO. Thus, 5‐LO product formation in PMNL induced by phosphorylation events was equally suppressed by CJ‐13,610 as compared to Ca2+‐mediated 5‐LO activation. In transfected HeLa cells, CJ‐13,610 only slightly discriminated between phosphorylatable wild‐type 5‐LO and a 5‐LO mutant that lacks phosphorylation sites.
In summary, CJ‐13,610 may possess considerable potential as a potent orally active nonredox‐type 5‐LO inhibitor that lacks certain disadvantages of former representatives of this class of 5‐LO inhibitors.
British Journal of Pharmacology (2004) 142, 861–868. doi:10.1038/sj.bjp.0705860
DOI: 10.1038/sj.bjp.0705860
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