title: Inhibition of 5-oxo-6,8,11,14-eicosatetraenoic acid-induced activation of neutrophils and eosinophils by novel indole OXE receptor antagonists.
abstract: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a 5-lipoxygenase product that is a potent granulocyte chemoattractant, which induces the infiltration of eosinophils into human skin when injected intradermally. It could therefore be an important proinflammatory mediator in eosinophilic diseases such as asthma and allergic rhinitis, and the OXE receptor, which mediates its actions, is therefore an attractive drug target. Using a structure-based approach in which substituents mimicking the essential polar (C1-C5) and hydrophobic (C15-C20) regions of 5-oxo-ETE were incorporated on an indole scaffold, we identified two potent selective OXE antagonists with IC50 values of about 30 nM. Neither compound displayed agonist activity and both inhibited 5-oxo-ETE-induced chemotaxis and actin polymerization and were relatively resistant to metabolism by rat liver homogenates. The active enantiomers of these racemic antagonists were even more potent, with IC50 values of <10 nM. These selective OXE antagonists could potentially be useful therapeutic agents in allergic diseases such as asthma.
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University , 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
authors.forename: Vivek
authors.initials: V
authors.lastname: Gore
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gravel
authors.forename: Chantal
authors.initials: C
authors.lastname: Cossette
authors.forename: Pranav
authors.initials: P
authors.lastname: Patel
authors.forename: Shishir
authors.initials: S
authors.lastname: Chourey
authors.forename: Qiuji
authors.initials: Q
authors.lastname: Ye
authors.forename: Joshua
authors.initials: J
authors.lastname: Rokach
authors.forename: William S
authors.initials: WS
authors.lastname: Powell
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D018716:Molecular Mimicry; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D058105:Polymerization; D051381:Rats; D018055:Receptors, Eicosanoid / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000199:Actins; D001095:Arachidonic Acids; D007211:Indoles; D018055:Receptors, Eicosanoid; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid