Interference of alpha-alkyl-substituted pirinixic acid derivatives with neutrophil functions and signalling pathways.
Pirinixic acid (Wy-14,643) is an agonist of the peroxisome proliferator-activated receptor (PPAR) subtype alpha exhibiting beneficial effects in various inflammation-related processes in a slow, long-termed fashion. We recently showed that alpha-substituted pirinixic acid derivatives are agonists of PPAR alpha and act as dual inhibitors of 5-lipoxygenase (5-LO, EC 1.13.11.34) and the microsomal prostaglandin E(2) synthase-1 (EC 5.3.99.3). Here, we explored short-term effects of alpha-substituted pirinixic acid derivatives on typical neutrophil functions evoked by the agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP) including leukotriene formation, generation of reactive oxygen species, and release of human leukocyte elastase (EC 3.4.21.37), and we investigated the modulation of related signalling pathways. Pirinixic acid derivatives that are substituted with alkyl residues in alpha-position of the carboxylic group and with a 6-aminoquinoline residue at the pyrimidine moiety cause inhibition of leukotriene formation, reactive oxygen species formation, and leukocyte elastase release in response to fMLP. In parallel, Ca(2+) mobilisation and the phosphorylation (activation) of p38 mitogen-activated protein kinase was significantly reduced, whereas phosphorylation of the extracellular signal-regulated kinase-2 was unaffected. Pirinixic acid itself was not or only marginally active in all these assays. Conclusively, targeted structural modification of pirinixic acid leads to bioactive compounds that display immediate anti-inflammatory properties in human neutrophils with potential therapeutic value.
Poeckel
Daniel
D
Department of Pharmaceutical Analytics, Institute of Pharmacy, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
Greiner
Christine
C
Pergola
Carlo
C
Henkel
Arne
A
Popescu
Laura
L
Rau
Oliver
O
Schubert-Zsilavecz
Manfred
M
Werz
Oliver
O
D000328:Adult; D000473:Alkanes / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000473:Alkanes; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D009240:N-Formylmethionine Leucyl-Phenylalanine; C006253:pirinixic acid; D048051:p38 Mitogen-Activated Protein Kinases; D010196:Pancreatic Elastase; D002118:Calcium