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1.
This study evaluated different concentrations of selective serotonin-reuptake inhibitors (citalopram and sertraline) for genotoxicity by use of the somatic mutation and recombination test (SMART) in Drosophila melanogaster. Three-day-old larvae, trans-heterozygous for the multiple wing hairs (mwh) and flare (flr3) genes were treated with these two compounds. Two recessive markers were located on the left arm of chromosome 3, i.e. 'multiple wing hairs' (mwh) in map position 0.3 and 'flare-3' (flr3) at 38.8, while the centromere was located in position 47.7. SMART is based on the loss of heterozygosity, which may occur through various mechanisms, such as mitotic recombination, mutation, deletion, half-translocation, chromosome loss, and non-disjunction. Genetic changes occurring in somatic cells of the wing's imaginal discs, cause the formation of mutant clones on the wing blade. The results of this study show that citalopram had a genotoxic effect in the Drosophila SMART. Sertraline, however, did not show any genotoxic effect in balancer heterozygous wings. This study concluded that more information is needed to be certain regarding the mutagenic effects of sertraline. 相似文献
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Paul A. Bethel Stefan Gerhardt Emma V. Jones Peter W. Kenny Galith I. Karoutchi Andrew D. Morley Keith Oldham Neil Rankine Martin Augustin Stephan Krapp Hannes Simader Stefan Steinbacher 《Bioorganic & medicinal chemistry letters》2009,19(16):4622-4625
A number of molecular recognition features have been exploited in structure-based design of selective Cathepsin inhibitors. 相似文献
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Cherney RJ King BW Gilmore JL Liu RQ Covington MB Duan JJ Decicco CP 《Bioorganic & medicinal chemistry letters》2006,16(4):1028-1031
Novel sultam hydroxamates with potent MMP activity were transformed into potent TACE inhibitors, lacking MMP activity. To accomplish this we relied on structural differences between the MMP and TACE S1' pockets and the known advantageous fit of a 2-methyl-4-quinolinylmethoxyphenyl group into this region. From this approach, compound 7d was identified as a potent TACE inhibitor (IC50 = 3.7 nM) that lacked MMP-1, -2, -9, and -13 activity. 相似文献
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Reverse hydroxamate-based selective TACE inhibitors 总被引:1,自引:0,他引:1
Kamei N Tanaka T Kawai K Miyawaki K Okuyama A Murakami Y Arakawa Y Haino M Harada T Shimano M 《Bioorganic & medicinal chemistry letters》2004,14(11):2897-2900
Reverse hydroxamate-based selective TACE inhibitors are described. They have potent TACE inhibitory activities and excellent selectivities against MMP-1, 2, 3, 8, 9, 13, 14, and 17. One representative compound, 18 has demonstrated an excellent oral inhibitory activity of the lipopolysaccharide (LPS)-stimulated TNF-alpha production in rats. 相似文献
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Serra S Ferino G Matos MJ Vázquez-Rodríguez S Delogu G Viña D Cadoni E Santana L Uriarte E 《Bioorganic & medicinal chemistry letters》2012,22(1):258-261
A series of 3-aryl-4-hydroxycoumarin derivatives was synthesized with the aim to find out the structural features for the MAO inhibitory activity and selectivity. Methoxy and/or chloro substituents were introduced in the 3-phenyl ring, whereas the position 6 in the coumarin moiety was not substituted or substituted with a methyl group or a chloro atom due to their different electronic, steric and/or lipophilic properties. Most of the synthesized compounds presented MAO-B inhibitory activity. The presence of methoxy and chloro groups, respectively in the para and meta positions of the 3-phenyl ring, have an important influence on the inhibitory activity. Moreover, the presence of a chloro atom in the six position of the moiety (compound 7) improved the inhibitor activity as well as its selectivity against MAO-B compared with iproniazide, used as reference compound. Docking experiments were carried out to understand which are the most energetically preferred orientations adopted by compounds 5, 6 and 7 inside the MAO-B binding pocket. 相似文献
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Murray M. Finkelstein 《CMAJ》2008,178(9):1185-1186
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Pyridazinones as selective cyclooxygenase-2 inhibitors 总被引:4,自引:0,他引:4
Li CS Brideau C Chan CC Savoie C Claveau D Charleson S Gordon R Greig G Gauthier JY Lau CK Riendeau D Thérien M Wong E Prasit P 《Bioorganic & medicinal chemistry letters》2003,13(4):597-600
Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and rat pyresis models, have been obtained. 相似文献
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Ortar G Schiano Moriello A Cascio MG De Petrocellis L Ligresti A Morera E Nalli M Di Marzo V 《Bioorganic & medicinal chemistry letters》2008,18(9):2820-2824
A new series of 1,5- and 2,5-disubstituted tetrazoles have been synthesized and evaluated as inhibitors of anandamide cellular uptake. Some of them inhibit the uptake process with a relatively high potency (IC50 = 2.3–5.1 μM) and selectively over other proteins involved in endocannabinoid action and metabolism. 相似文献
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Kozak KR Prusakiewicz JJ Rowlinson SW Marnett LJ 《Bioorganic & medicinal chemistry letters》2002,12(9):1315-1318
Cyclooxygenase inhibition studies with novel indomethacin alkanolamides demonstrate the potential for dramatic differences in inhibitor properties conferred by subtle structural modifications. The transformation of non-selective alpha-(S)-substituted indomethacin ethanolamides to potent, COX-2 selective inhibitors by simple stereocenter inversion highlights this property. 相似文献
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Shinozuka T Shimada K Matsui S Yamane T Ama M Fukuda T Taki M Takeda Y Otsuka E Yamato M Mochizuki S Ohhata K Naito S 《Bioorganic & medicinal chemistry》2006,14(20):6789-6806
A novel series of cathepsin K inhibitors derived from Novartis compound I is described. Optimization of the P1, P3, and P1' units led to the identification of 4-aminophenoxyacetic acid 24b with an IC(50) value of 4.8 nM, which possessed an excellent selectivity over other human cathepsins and good pharmacokinetic (PK) properties. Oral administration of compound 24b to ovariectomized (OVX) rats showed a trend toward an improvement of bone mineral density (BMD) in the femur bone. 相似文献
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Cywin CL Dahmann G Prokopowicz AS Young ER Magolda RL Cardozo MG Cogan DA Disalvo D Ginn JD Kashem MA Wolak JP Homon CA Farrell TM Grbic H Hu H Kaplita PV Liu LH Spero DM Jeanfavre DD O'Shea KM White DM Woska JR Brown ML 《Bioorganic & medicinal chemistry letters》2007,17(1):225-230
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds. 相似文献
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Tang W Luo T Greenberg EF Bradner JE Schreiber SL 《Bioorganic & medicinal chemistry letters》2011,21(9):2601-2605
We have developed an efficient method for synthesizing candidate histone deacetylase (HDAC) inhibitors in 96-well plates, which are used directly in high-throughput screening. We selected building blocks having hydrazide, aldehyde and hydroxamic acid functionalities. The hydrazides were coupled with different aldehydes in DMSO. The resulting products have the previously identified ‘cap/linker/biasing element’ structure known to favor inhibition of HDACs. These compounds were assayed without further purification. HDAC8-selective inhibitors were discovered from this novel collection of compounds. 相似文献
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Kenji Naganuma Akifumi Omura Naomi Maekawara Masahiro Saitoh Naoto Ohkawa Takashi Kubota Hiromitsu Nagumo Toshiyuki Kodama Masayoshi Takemura Yuji Ohtsuka Junji Nakamura Ryuichi Tsujita Koh Kawasaki Hirotsugu Yokoi Masashi Kawanishi 《Bioorganic & medicinal chemistry letters》2009,19(12):3174-3176
In this study the first PDE4B selective inhibitor is described. Optimization of lead 2-arylpyrimidine derivatives afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, a selected compound exhibited potent anti-inflammatory effects in vivo and showed less emesis compared with Cilomilast. 相似文献
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Discovery of selective small-molecule CD80 inhibitors 总被引:1,自引:0,他引:1
Uvebrant K da Graça Thrige D Rosén A Akesson M Berg H Walse B Björk P 《Journal of biomolecular screening》2007,12(4):464-472
Protein-protein interactions are widely found in biological systems controlling diverse cellular events. Because these interactions are implicated in many diseases such as autoimmunity and cancer, regulation of protein-protein interactions provides ideal targets for drug intervention. The CD80-CD28 costimulatory pathway plays a critical role in regulation of the immune response and thus constitutes an attractive target for therapeutic manipulation of autoimmune diseases. The objective of this study is to identify small compounds disrupting these pivotal protein-protein interactions. Compounds that specifically blocked binding of CD80 to CD28 were identified using a strategy involving a cell-based scintillation proximity assay as the initial step. Secondary screening (e.g., by analyzing the direct binding of these compounds to the target immobilized on a biosensor surface) revealed that these compounds are highly selective CD80 binders. Screening of structurally related derivatives led to the identification of the chemical features required for inhibition of the CD80-CD28 interaction. In addition, the optimization process led to a 10-fold increase in binding affinity of the CD80 inhibitors. Using this approach, the authors identify low-molecular-weight compounds that specifically and with high potency inhibit the interaction between CD80 and CD28. These compounds serve as promising starting points for further development of CD80 inhibitors as potential immunomodulatory drugs. 相似文献
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Potent selective inhibitors of protein kinase C 总被引:21,自引:0,他引:21
P D Davis C H Hill E Keech G Lawton J S Nixon A D Sedgwick J Wadsworth D Westmacott S E Wilkinson 《FEBS letters》1989,259(1):61-63
A series of potent, selective inhibitors of protein kinase C has been derived from the structural lead provided by the microbial broth products, staurosporine and K252a. Our inhibitors block PCK in intact cells (platelets and T cells), and prevent the proliferation of mononuclear cells in response to interleukin 2 (IL2). 相似文献
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AIM To identify neuron-selective androgen receptor(AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy(SBMA), or Kennedy's disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell typeselective AR inhibitors. Secondary screening in luciferase assays was used to identify the best cell-type specific AR inhibitors. The mechanism of action of a neuronselective AR inhibitor was examined in vitro using luciferase reporter assays, immunofluorescence microscopy, and immunoprecipitations. Rats were treated with the most potent compound and tissue-selective AR inhibition was examined using RT-q PCR of AR-regulated genes and immunohistochemistry.RESULTS We identified the thiazole class of antibiotics as com-pounds able to inhibit AR signaling in a neuronal cell line but not a muscle cell line. One of these antibiotics, thiostrepton is able to inhibit the activity of both wild type and polyglutamine expanded AR in neuronal GT1-7 cells with nanomolar potency. The thiazole antibiotics are known to inhibit FOXM1 activity and accordingly, a novel FOXM1 inhibitor FDI-6 also inhibited AR activity in a neuron-selective fashion. The selective inhibition of AR is likely indirect as the varied structures of these compounds would not suggest that they are competitive antagonists. Indeed, we found that FOXM1 expression correlates with cell-type selectivity, FOXM1 co-localizes with AR in the nucleus, and that sh RNA-mediated knock down of FOXM1 reduces AR activity and thiostrepton sensitivity in a neuronal cell line. Thiostrepton treatment reduces FOXM1 levels and the nuclear localization of beta-catenin, a known co-activator of both FOXM1 and AR, and reduces the association between beta-catenin and AR. Treatment of rats with thiostrepton demonstrated AR signaling inhibition in neurons, but not muscles. CONCLUSION Our results suggest that thiazole antibiotics, or other inhibitors of the AR-FOXM1 axis, can inhibit AR signaling selectively in motor neurons and may be useful in the treatment or prevention of SBMA symptoms. 相似文献