共查询到20条相似文献,搜索用时 15 毫秒
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David A. Sandham Nicola Arnold Heinrich Aschauer Kamlesh Bala Lucy Barker Lyndon Brown Zarin Brown David Budd Brian Cox Cerys Docx Gerald Dubois Nicholas Duggan Karen England Brian Everatt Marcus Furegati Edward Hall Frank Kalthoff Anna King Caroline Wilson 《Bioorganic & medicinal chemistry》2013,21(21):6582-6591
Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development. 相似文献
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Hyun Jung Min Young Choong Kim Mi Ran Byun Jeong-Ho Hong 《Biochemical and biophysical research communications》2009,385(2):204-149
Sauchinone, a lignan compound isolated from the root of Saururus chinensis, has been recently demonstrated to exhibit anti-inflammatory activity via the suppression of NF-kB p65 activity in vitro. In an effort to evaluate the in vivo anti-inflammatory function of sauchinone, we have evaluated the effects of sauchinone on allergen-induced airway inflammation using a murine model of allergic asthma. We observed that marked eosinophilic and lymphocyte infiltration in the BAL fluid were suppressed to a significant degree by sauchinone, and that mucus-secreting goblet cell hyperplasia and collagen deposition in the airways were also ameliorated by administration of sauchinone treatment. Moreover, gene expression of the inflammatory cytokines, IL-13, and IL-5 and eotaxin in the lung, and IL-5 in the draining lymph node were significantly decreased in sauchinone-treated mice. We demonstrated that sauchinone repressed Th2 cell development in vitro and IL-4 production by Th2 cells, and also inhibited GATA-3-mediated IL-5 promoter activity in a dose-dependent manner. Collectively, sauchinone ameliorated allergen-induced airway inflammation, in part, by repressing GATA-3 activity for Th2 cell development, indicating the possible therapeutic potential of sauchinone in airway inflammatory diseases including allergic asthma and rhinitis. 相似文献
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Luker T Bonnert R Schmidt J Sargent C Paine SW Thom S Pairaudeau G Patel A Mohammed R Akam E Dougall I Davis AM Abbott P Brough S Millichip I McInally T 《Bioorganic & medicinal chemistry letters》2011,21(12):3616-3621
A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34. 相似文献
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Luker T Bonnert R Brough S Cook AR Dickinson MR Dougall I Logan C Mohammed RT Paine S Sanganee HJ Sargent C Schmidt JA Teague S Thom S 《Bioorganic & medicinal chemistry letters》2011,21(21):6288-6292
Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22). 相似文献
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Kosaka-Suzuki N Suzuki T Pugacheva EM Vostrov AA Morse HC Loukinov D Lobanenkov V 《The Journal of biological chemistry》2011,286(31):27378-27388
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P. H. Steenbergh E. Jansen F. M. A. Van Schaik J. S. Sussenbach 《Molecular reproduction and development》1993,35(4):365-367
The two putative promoter regions of the human insulin-like growth factor-I (IGF-I) gene, located upstream of the two alternatively used leader exons 1 and 2, were tested for promoter activity in transient transfection assays. Both regions were shown to possess promoter activity. The results further indicate cell-type-specific regulation of the activities of the two promoters in endogenously IGF-I producing human cell lines of different origin. © 1993 Wiley-Liss, Inc. 相似文献
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Scott JM Baccei C Bain G Broadhead A Evans JF Fagan P Hutchinson JH King C Lorrain DS Lee C Prasit P Prodanovich P Santini A Stearns BA 《Bioorganic & medicinal chemistry letters》2011,21(21):6608-6612
Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D(2) receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eosinophil shape change assay, as well as good oral bioavailability in rat and dog, and efficacy in a mouse model of allergic rhinitis following oral dosing. 相似文献
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The Wcs120 gene encodes a highly abundant protein which appears to play an important role during cold acclimation of wheat. To understand
the regulatory mechanism controlling its expression at low temperature, the promoter region has been characterized. Electrophoretic
mobility shift assays using short promoter fragments revealed the presence in nuclear extracts from non-acclimated (NA) plants
of multiple DNA-binding proteins which interact with several elements. In contrast, no DNA-binding activity was observed in
the nuclear extracts from cold-acclimated (CA) plants. In vitro dephosphorylation of these CA nuclear extracts with alkaline
phosphatase restored the binding activity. Moreover, okadaic acid (a potent phosphatase inhibitor) markedly stimulated the
in vivo accumulation of the WCS120 family of proteins. This suggests that protein phosphatases PP1 and/or PP2A negatively
regulate the expression of the Wcs120 gene. In addition, both Ca2+-dependent and Ca2+-independent kinase activities were found to be significantly higher in the CA nuclear extracts. Western analysis using antibodies
directed against protein kinase C (PKC) isoforms showed that a PKCγ homolog (84 kDa) is selectively translocated into the
nucleus in response to low temperature. Taken together, our results suggest that, in vivo, the expression of the Wcs120 gene may be regulated by nuclear factors whose binding activity is modulated by a phosphorylation/dephosphorylation mechanism.
Received: 9 June 1997 / Accepted: 18 August 1997 相似文献
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I Virgolini S Li C Sillaber O Majdic H Sinzinger K Lechner P Bettelheim P Valent 《The Journal of biological chemistry》1992,267(18):12700-12708
Recent data suggest that prostaglandins (PGs) are involved in the regulation of basophil activation. The aim of this study was to characterize the basophil PG-binding sites by means of radioreceptor assays using 3H-labeled PGs. Scatchard analysis for pure (greater than 95%) chronic myeloid leukemia (CML) basophils revealed two classes of PGE1-binding sites differing in their affinity for the natural ligand (Bmax1 = 217 +/- 65 fmol/10(8) cells; Kd1 = 0.5 +/- 0.2 nM; Bmax2 = 2462 +/- 381 fmol/10(8) cells; Kd2 = 47 +/- 20 nM; IC50 = PGE1 less than PGI2 less than PGD2 less than PGE2 less than PGF2 alpha) as well as two classes of PGI2 (iloprost)-binding sites (Bmax1 = 324 +/- 145 fmol/10(8) cells; Kd1 = 0.5 +/- 0.3 nM; Bmax2 = 2541 +/- 381; Kd2 = 27 +/- 6 nM; IC50 = PGI2 less than PGE1 less than PGD2 less than PGE2 less than PGF2 alpha. In addition, CML basophils exhibited a single class of PGD2-binding sites (Bmax = 378 +/- 98 fmol/10(8) cells; Kd = 13 +/- 4 nM; IC50: PGD2 less than PGI2 less than PGE1 less than PGE2 less than PGF2 alpha). In contrast, we were unable to detect specific saturable PGE2-binding sites. Primary and immortalized (KU812) CML basophils revealed an identical pattern of PG receptor expression. Basophils (KU812) expressed significantly (p less than 0.001) lower number of PGE1 (PGI2)-binding sites (Bmax1: 9% (20%) of control; Bmax2: 36% (50%) of control) when cultured with recombinant interleukin 3 (rhIL-3), a basophil-activating cytokine, whereas rhIL-2 had no effect on PG receptor expression. Functional significance of binding of PGs to basophils was provided by the demonstration of a dose-dependent increase in cellular cAMP upon agonist activation, with PGE1 (ED50 = 1.7 +/- 1.1 nM) and PGI2 (ED50 = 2.8 +/- 2.3 nM) being the most potent compounds. These findings suggest that human basophils express specific receptors for PGE1, PGI2 as well as for PGD2. 相似文献