UM
4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists
Kirpotina, Liliya N.; Schepetkin, Igor A.; Khlebnikov, Andrei I.; Ruban, Olga I.; Ge, Yunjun; Ye, Richard D.; Kominsky, Douglas J.; Quinn, Mark T.
2017-10-15
Source PublicationBIOCHEMICAL PHARMACOLOGY
ISSN0006-2952
Volume142Pages:120-132
AbstractFormyl peptide receptors (FPRs) are expressed on a variety of leukocytes and play important roles in inflammation. Thus, FPR antagonists may represent novel therapeutics for modulating innate immunity and treating inflammatory diseases. Previously, 1H-pyrrol-2(5H)-ones were reported to be potent and competitive FPR1 antagonists. In the present studies, 42 additional 1H-pyrrol-2(5H)-one analogs were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited N-formylmethionyl-leucyl-phenylalanine (fMLF)-induced intracellular Ca2+ mobilization in FPR1-transfected HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-transfected RBL cells. The most active pyrroles inhibited human neutrophil Ca2+ flux, chemotaxis, and adhesion to human epithelial cells, with the most potent being compounds 14 (4-benzoyl-1-hexyl-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-2,5-dihydro-1H-pyrrol-2-one) and 17 (4-benzoy1-5-(2,5dimethoxyphenyl)-3-hydroxy-1-(2-methoxyethyl)-2,5-dihydro-1H-pyrrol-2-one). In addition, these FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPRI-RBL cells, differentiated HL-60 cells, and human neutrophils. Most of the antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, or interleukin 8-induced Ca2+ flux in human neutrophils. Moreover, molecular modeling showed that the active pyrroles had a significantly higher degree of similarity with the FPR1 antagonist pharmacophore template as compared to inactive analogs. Thus, the 4-aroyl-3hydroxy-5-phenyl-IH-pyrrol-2(5H)-one scaffold represents an important backbone for the development of novel FPR1 antagonists and could provide important clues for understanding the molecular structural requirements of FPR1 antagonists. (C) 2017 Elsevier Inc. All rights reserved.
KeywordAntagonist Formyl peptide receptor 1H-pyrrol-2(5H)-one Neutrophil Molecular modeling
DOI10.1016/j.bcp.2017.07.004
URLView the original
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000412152300011
PublisherPERGAMON-ELSEVIER SCIENCE LTD
The Source to ArticleWOS
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Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
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GB/T 7714
Kirpotina, Liliya N.,Schepetkin, Igor A.,Khlebnikov, Andrei I.,et al. 4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists[J]. BIOCHEMICAL PHARMACOLOGY,2017,142:120-132.
APA Kirpotina, Liliya N..,Schepetkin, Igor A..,Khlebnikov, Andrei I..,Ruban, Olga I..,Ge, Yunjun.,...&Quinn, Mark T..(2017).4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists.BIOCHEMICAL PHARMACOLOGY,142,120-132.
MLA Kirpotina, Liliya N.,et al."4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists".BIOCHEMICAL PHARMACOLOGY 142(2017):120-132.
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