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|---|---|---|---|
| 001 | 656904 | ||
| 005 | 20231030041449.0 | ||
| 035 | _a(RuTPU)RU\TPU\network\23384 | ||
| 090 | _a656904 | ||
| 100 | _a20171220a2017 k y0engy50 ba | ||
| 101 | 0 | _aeng | |
| 102 | _aNL | ||
| 135 | _adrcn ---uucaa | ||
| 181 | 0 | _ai | |
| 182 | 0 | _ab | |
| 200 | 1 |
_a4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists _fL. N. Kirpotina, I. A. Shchepyotkin, A. I. Khlebnikov [et al.] |
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| 203 |
_aText _celectronic |
||
| 300 | _aTitle screen | ||
| 320 | _a[References: p. 131-132 (55 tit.)] | ||
| 330 | _aFormyl 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-benzoyl-5-(2,5-dimethoxyphenyl)-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 FPR1-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-3-hydroxy-5-phenyl-1H-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. | ||
| 333 | _aРежим доступа: по договору с организацией-держателем ресурса | ||
| 461 | _tBiochemical Pharmacology | ||
| 463 |
_tVol. 142 _v[P. 120-132] _d2017 |
||
| 610 | 1 | _aэлектронный ресурс | |
| 610 | 1 | _aтруды учёных ТПУ | |
| 610 | 1 | _aantagonist | |
| 610 | 1 | _aformyl peptide receptor | |
| 610 | 1 | _aneutrophil | |
| 610 | 1 | _amolecular modeling | |
| 610 | 1 | _aантагонист | |
| 610 | 1 | _aформил-пептиды | |
| 610 | 1 | _aпирролы | |
| 610 | 1 | _aнейтрофилы | |
| 610 | 1 | _aмолекулярное моделирование | |
| 701 | 1 |
_aKirpotina _bL. N. _gLiliya Nikolaevna |
|
| 701 | 1 |
_aShchepyotkin _bI. A. _cdoctor-biophysicist _cleading researcher of Tomsk Polytechnic University, candidate of medical science _f1962- _gIgor Aleksandrovich _2stltpush _3(RuTPU)RU\TPU\pers\37358 |
|
| 701 | 1 |
_aKhlebnikov _bA. I. _cChemist _cProfessor of Tomsk Polytechnic University _f1963- _gAndrey Ivanovich _2stltpush _3(RuTPU)RU\TPU\pers\33927 |
|
| 701 | 1 |
_aRuban _bO. I. _gOlga Ivanovna |
|
| 701 | 0 | _aGe Yunjun | |
| 701 | 1 |
_aYe _bR. D. _gRichard |
|
| 701 | 1 |
_aKominsky _bD. J. _gDouglas |
|
| 701 | 1 |
_aQuinn _bM. T. _gMark |
|
| 712 | 0 | 2 |
_aНациональный исследовательский Томский политехнический университет (ТПУ) _bУправление проректора по научной работе и инновациям (НРиИ) _bЦентр RASA в Томске _bЛаборатория изучения механизмов нейропротекции (Лаб. ИМН) _h7608 _2stltpush _3(RuTPU)RU\TPU\col\21815 |
| 712 | 0 | 2 |
_aНациональный исследовательский Томский политехнический университет (ТПУ) _bИнститут физики высоких технологий (ИФВТ) _bКафедра биотехнологии и органической химии (БИОХ) _h6810 _2stltpush _3(RuTPU)RU\TPU\col\18693 |
| 801 | 2 |
_aRU _b63413507 _c20201103 _gRCR |
|
| 856 | 4 | _uhttps://doi.org/10.1016/j.bcp.2017.07.004 | |
| 942 | _cCF | ||