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101.
Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach
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Dr. Bibia Heidmann Dr. John Gatfield Dr. Catherine Roch Dr. Alexander Treiber Dr. Simone Tortoioli Dr. Christine Brotschi Dr. Jodi T. Williams Dr. Martin H. Bolli Dr. Stefan Abele Dr. Thierry Sifferlen Dr. François Jenck Dr. Christoph Boss 《ChemMedChem》2016,11(19):2132-2146
Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold‐hopping approach. Structure–activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time‐dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P‐glycoprotein (Pgp)‐mediated efflux. Compound 80 c [{(1S,6R)‐3‐(6,7‐difluoroquinoxalin‐2‐yl)‐3,8‐diazabicyclo[4.2.0]octan‐8‐yl}(4‐methyl‐[1,1′‐biphenyl]‐2‐yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium‐release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep‐promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant. 相似文献
102.
Mallory Batty Rachel Pugh Ilampirai Rathinam Joshua Simmonds Edwin Walker Amanda Forbes Shailendra Anoopkumar-Dukie Catherine M. McDermott Briohny Spencer David Christie Russ Chess-Williams 《International journal of molecular sciences》2016,17(8)
This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. 相似文献
103.
Venkat N. Vangaveti Venkatesh M. Shashidhar Catherine Rush Usman H. Malabu Roy R. Rasalam Fiona Collier Bernhard T. Baune Richard L. Kennedy 《Lipids》2014,49(12):1181-1192
Macrophage apoptosis, a key process in atherogenesis, is regulated by oxidation products, including hydroxyoctadecadienoic acids (HODEs). These stable oxidation products of linoleic acid (LA) are abundant in atherosclerotic plaque and activate PPARγ and GPR132. We investigated the mechanisms through which HODEs regulate apoptosis. The effect of HODEs on THP‐1 monocytes and adherent THP‐1 cells were compared with other C18 fatty acids, LA and α‐linolenic acid (ALA). The number of cells was reduced within 24 hours following treatment with 9‐HODE (p < 0.01, 30 μM) and 13 HODE (p < 0.01, 30 μM), and the equivalent cell viability was also decreased (p < 0.001). Both 9‐HODE and 13‐HODE (but not LA or ALA) markedly increased caspase‐3/7 activity (p < 0.001) in both monocytes and adherent THP‐1 cells, with 9‐HODE the more potent. In addition, 9‐HODE and 13‐HODE both increased Annexin‐V labelling of cells (p < 0.001). There was no effect of LA, ALA, or the PPARγ agonist rosiglitazone (1μM), but the effect of HODEs was replicated with apoptosis‐inducer camptothecin (10μM). Only 9‐HODE increased DNA fragmentation. The pro‐apoptotic effect of HODEs was blocked by the caspase inhibitor DEVD‐CHO. The PPARγ antagonist T0070907 further increased apoptosis, suggestive of the PPARγ‐regulated apoptotic effects induced by 9‐HODE. The use of siRNA for GPR132 showed no evidence that the effect of HODEs was mediated through this receptor. 9‐HODE and 13‐HODE are potent—and specific—regulators of apoptosis in THP‐1 cells. Their action is PPARγ‐dependent and independent of GPR132. Further studies to identify the signalling pathways through which HODEs increase apoptosis in macrophages may reveal novel therapeutic targets for atherosclerosis. 相似文献
104.
Poly(Tetrasubstituted Aryl Imidazole)s (PTAIs), a new class of poly(heteroaromatic) polymers was prepared via a cascade polycondensation process, under microwave irradiation. These polymers were obtained by the tetrasubstituted aryl imidazole ring formation involving bis(aryl α-diketone)s, bis(arylaldehyde)s, mono(arylamine)s and ammonium acetate. The polymerization performed under microwave irradiation allowed to get high molecular weight PTAIs in very short reaction times. The chemical structure of these PTAIs was confirmed by NMR spectroscopy. Thermogravimetric analyses (TGA) showed a very good grade of thermal stability of these polymers. Glass transition temperatures (Tg) of PTAIs ranging from 155 °C to 265 °C were determined by Differential Scanning Calorimetry (DSC). 相似文献
105.
Ian Mabbett Jon Elvins Catherine Gowenlock Carol Glover Paul Jones Geraint Williams David Worsley 《Progress in Organic Coatings》2014
Near infrared (NIR) is becoming a popular option for rapid cure of coatings in the coil coating industry particularly where fast line speeds are required. The technology has the potential to reduce the cure time of a 20 μm polyester coating on a galvanised steel substrate from around 30 s via conventional heating methods down to <10 s under the lamps. Previous work suggested that the ideal situation in this case is to have a topcoat which is slightly transparent to NIR and an absorbing substrate to heat the coating from the substrate outwards in a two stage process which separates solvent removal from cross linking and film formation. This can be taken further by tinting the primer layer with a pigment that absorbs in the NIR region. In this study spectroscopy was used to show that a coated steel system could appear white in the visible region because of the reflectance of TiO2 but the NIR absorption could be altered by adding absorbing pigments such as carbon black. Lamp settings could be reduced by 20% to achieve equivalent cure with tinted primer systems. The potential degradation in corrosion protection afforded by carbon-black containing pigments at various loadings was assessed for model organic coatings applied to galvanised steel specimens. In situ scanning Kelvin probe studies showed that rates of corrosion-driven coating delamination by cathodic disbondment remained unchanged by pigment loadings of up to 3.5 wt%. 相似文献
106.
107.
108.
Preparation of conjugated linoleic acid from safflower oil 总被引:5,自引:0,他引:5
David W. L. Ma Antoni A. Wierzbicki Catherine J. Field Michael T. Clandinin 《Journal of the American Oil Chemists' Society》1999,76(6):729-730
Synthetically prepared mixtures of conjugated linoleic acid (CLA) are widely used in animal and cell culture studies to investigate
the potential effects of the Δ9c, 11t-18:2 isomer found in food products from ruminant animals. Alkali isomerization of linoleic acid is a common method used in
the synthesis of a mixture of CLA isomers containing predominantly the Δ9c, 11t-18:2 and Δ10t, 12c-18:2 isomers. Some biological activity might also be mediated by the Δ10t, 12c-18:2 isomer. Currently few published methodologies exist describing procedures for the enrichment of these two isomers. A
method is described herein to take advantage of an inexpensive oil, safflower oil, for use in synthesis of CLA and a procedure
to enrich the Δ10t, 12c-18:2 isomer. 相似文献
109.
Metal contamination of urban soils in the vicinity of a municipal waste incinerator: one source among many 总被引:7,自引:0,他引:7
Rimmer DL Vizard CG Pless-Mulloli T Singleton I Air VS Keatinge ZA 《The Science of the total environment》2006,356(1-3):207-216
Concern from local residents about possible contamination with metals and PCDD/F (dioxins and furans) from fugitive and stack emissions from the Byker municipal solid waste incinerator in Newcastle upon Tyne led the City Council to initiate a study of the concentration of these pollutants in soils. We report here the results for the metals and arsenic. Soils were sampled at distances up to 2.25 km from the incinerator stack. The intensity of sampling in concentric zones was four times greater in the northeast (down-wind) direction, and twice as great in the northwest and southeast directions, compared to the southwest (up-wind) direction. In total 163 samples were collected and analyzed for total As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn. Concentrations were generally elevated above background levels, but were typical of those found in other urban areas. For As, Cd, Cu, Hg, Pb, and Zn, contamination hotspots were identified. These were spread throughout the sampling area, and there was no evidence of greater concentrations down-wind of the incinerator compared to other directions, nor of any trend in concentration at increasing distance from the incinerator. We concluded that metal contamination resulting from the incinerator could not be detected in an environment with generally elevated concentrations. Potential sources for many of the hotspots of contamination were identified in a survey of historic land use based on maps of the locality dating back to 1856. Detailed investigations of particular areas with serious contamination will now be undertaken by the local authorities using the CLEA (Contaminated Land Exposure Assessment) model. 相似文献
110.
20世纪80年代,瑞典农业科学大学风景园林系教授罗朗·古斯塔文森在阿尔纳普校区创建风景实验室,融汇三脉斯堪的纳维亚风景园林的历史源流,即农林、早期自然保护与城市公园,系统性、全尺度地探索一片幼林地风景的创造性管理。风景实验室将林地规划为多林分组合,作为营林、风景园林设计与教学,以及公共游览的同一场所,因循植物景观的自然形态与活态结构,善用林室氛围景观,实践一种协同营林、生态保育和风景审美效用的管理式设计,为发展多用途城市林地提供创新实验场所。在风景实验室教研组发表的项目论文与报告书等文献资料的基础上,说明主要实验原则与方法,解析创造性管理的风景园林设计主线,简述由风景实验室延伸出的设计概念与项目。 相似文献