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Beaulieu F Ouellet C Ruediger EH Belema M Qiu Y Yang X Banville J Burke JR Gregor KR MacMaster JF Martel A McIntyre KW Pattoli MA Zusi FC Vyas D 《Bioorganic & medicinal chemistry letters》2007,17(5):1233-1237
We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50 = 0.30 microM), which however was considerably less potent against IKK-1 (IC50 = 4.0 microM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of 1, we prepared a series of tetracyclic analogues (7, 13, and 18). The synthesis and biological activities of these potent IKK inhibitors are described. 相似文献
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Activation of myogenic differentiation pathways in adult bone marrow-derived stem cells 总被引:8,自引:0,他引:8
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Belema Bedada F Technau A Ebelt H Schulze M Braun T 《Molecular and cellular biology》2005,25(21):9509-9519
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Bertalan R Patocs A Vasarhelyi B Treszl A Varga I Szabo E Tamas J Toke J Boyle B Nobilis A Rigo J Racz K 《The Journal of steroid biochemistry and molecular biology》2008,111(1-2):91-94
Endogenous and exogenous glucocorticoids influence fetal growth and development, and maternal administration of synthetic glucocorticoids may decrease the risk of perinatal morbidity including lung disease in preterm neonates. Because polymorphisms of the glucocorticoid receptor gene are known to influence the sensitivity to glucocorticoids, in the present study we examined whether any associations could exist among the BclI, N363S and ER22/23EK polymorphisms of the glucocorticoid receptor gene and gestational age, birth weight and/or perinatal morbidity of 125 preterm neonates born at 28-35 weeks' gestation with (n=57) or without maternal dexamethasone treatment (n=68). The prevalence of the three polymorphisms in the whole group of preterm infants was similar to that reported in healthy adult Hungarian population. However, we found that the BclI polymorphism significantly associated with higher birth weight adjusted for the gestational age (p=0.004, ANOVA analysis). None of the three polymorphisms showed an association with perinatal morbidities, including necrotizing enterocolitis, intraventricular hemorrhagia, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia and sepsis in the two groups of preterm neonates with and without maternal dexamethasone treatment. These results suggest that the BclI polymorphism of the glucocorticoid receptor gene may have an impact on gestational age-adjusted birth weight, but it does not influence perinatal morbidities of preterm neonates. 相似文献
4.
Introduction
Glucocorticoid receptor (GR) is expressed in the normal human adrenal gland, however, no study has been performed to evaluate the separate expression of α- and β-isoforms (GRα and GRβ) in normal human adrenals and in adrenocortical adenomas.Experimental
GRα and GRβ mRNA expression was examined by quantitative real-time PCR in 31 adrenal tissues including 19 non-functioning adenomas (NFA), 6 cortisol-producing adenomas (CPA) and 6 normal adrenocortical tissues. In addition, the presence and cellular localization of GRα and GRβ proteins in adrenal tissues were studied by immunohistochemistry.Results
Compared to normal adrenocortical tissues, both GRα and GRβ mRNAs were significantly increased in CPA but not in NFA. Using anti-GRα antibody a strong nuclear staining was observed in NFA and CPA, and a less remarkable immunoreactivity was detected in some nuclei of normal adrenocortical cells. GRβ immunostaining was absent in normal adrenal tissues and NFA, while a strong cytoplasmic and nuclear immunoreaction was found in CPA.Conclusions
Altered expression of GRα and GRβ in CPA raises their possible role in the pathophysiology of these adrenal tumors, although further studies are needed to elucidate the potential significance of these findings. 相似文献5.
Belema M Bunker A Nguyen VN Beaulieu F Ouellet C Qiu Y Zhang Y Martel A Burke JR McIntyre KW Pattoli MA Daloisio C Gillooly KM Clarke WJ Brassil PJ Zusi FC Vyas DM 《Bioorganic & medicinal chemistry letters》2007,17(15):4284-4289
The identification of a potent series of IKK-beta selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-alpha release mouse model are described. 相似文献
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Makonen Belema Van N. Nguyen Denis R. St. Laurent Omar D. Lopez Yuping Qiu Andrew C. Good Peter T. Nower Lourdes Valera Donald R. O’Boyle Jin-Hua Sun Mengping Liu Robert A. Fridell Julie A. Lemm Min Gao Jay O. Knipe Nicholas A. Meanwell Lawrence B. Snyder 《Bioorganic & medicinal chemistry letters》2013,23(15):4428-4435
The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the initial program lead, stilbene 2a. Structure–activity relationship (SAR) studies that uncovered an alternate phenylglycine-based cap series that exhibit further improvements in virology profile, along with some insights into the pharmacophoric elements associated with the GT-1a potency, are described. 相似文献
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Omar D. Lopez Van N. Nguyen Denis R. St. Laurent Makonen Belema Michael H. Serrano-Wu Jason T. Goodrich Fukang Yang Yuping Qiu Amy S. Ripka Peter T. Nower Lourdes Valera Mengping Liu Donald R. O’Boyle Jin-Hua Sun Robert A. Fridell Julie A. Lemm Min Gao Andrew C. Good Lawrence B. Snyder 《Bioorganic & medicinal chemistry letters》2013,23(3):779-784
In a recent disclosure,1 we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting <10 nM EC50 in a genotype 1b replicon assay. 相似文献
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