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21.
Dr. Hui Qiu Richard Caldwell Dr. Lesley Liu-Bujalski Dr. Andreas Goutopoulos Reinaldo Jones Justin Potnick Dr. Brian Sherer Dr. Andrew Bender Dr. Roland Grenningloh Dr. Daigen Xu Dr. Anna Gardberg Dr. Igor Mochalkin Dr. Theresa Johnson Dr. Ariele Viacava Follis Jared Head Dr. Federica Morandi 《ChemMedChem》2019,14(2):217-223
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. 相似文献
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Porous polyimide (PI) films with low dielectric constants and excellent thermal properties have been a pressing demand for the next generation of high-performance, miniature, and ultrathin microelectronic devices. A series of novel porous PI films containing fluorenyl-adamantane groups were prepared successfully via thermolysis of poly(ethylene glycol) (PEG) added in the PI matrix. The cross-sectional morphologies of porous PI films showed closed pores with diameters ranging from 135 to 158 nm, which were uniform and regular in shape without interconnectivity. These porous PI films exhibited excellent thermal properties with a glass-transition temperature at 376 °C whereas the 5% weight loss temperature in air excess of 405 °C due to enhanced rigidity afforded by fluorenyl-adamantane groups. Accompanied by thermolysis content of PEG increasing from 0 to 20 wt %, the density of porous PI films decreased, and the corresponding porosity grew significantly from 0 to 11.48%. Depending on porosity, the dielectric constant and dielectric loss of porous PI films significantly declined from 2.89 to 2.37 and from 0.050 to 0.021, respectively. These excellent properties benefit the as-prepared porous PI films for application as interlayer dielectrics, integrated circuit chips, or multichip modules in microelectronic fields. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47313. 相似文献
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四川盆地上三叠统划分对比研究 总被引:36,自引:6,他引:30
四川盆地上三叠统对比长期存在混乱,给盆地整体评价带来困难。通过岩石地层、地震地层、事件地层及高分辨率旋回地层等多种方法讨论了须家河组与香溪群各岩性段的对比关系,得出了全盆地上三叠统的对比关系;指出须四段底可近似看成等时界面;须家河组下部地层自西向东、向南逐层超覆在雷口坡组之上,上部地层在盆地西北部自东南向西北方向剥蚀层位渐次变老。文章建议四川盆地上三叠统废除“香溪群”,统一使用“须家河组”,以利于对全盆地上三叠统进行油气资源整体评价与深化研究。 相似文献
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针对不同地质目标的叠前时间偏移成像解释评价 总被引:3,自引:0,他引:3
随着计算机硬件和地震勘探成像技术的发展,叠前时间偏移正逐步替代常规的NMO加DMO加叠后时间偏移成为地震数据成像处理方法的主流。但对于不同的地质目标,叠前时间偏移的成像效果是否优于常规NMO加DMO加叠后时间偏移的成像效果呢?为此,从地震数据成像处理方法、处理流程和处理参数等方面进行了讨论,并基于某地区三维数据常规处理结果和叠前时间偏移处理结果,针对不同地质目标进行了剖析与评价。认为:叠前时间偏移成像的垂向分辨率较常规处理明显降低,但对于空间波阻抗变化明显的河流和断层,叠前时间偏移成像的空间分辨率要高于常规处理;对于小于1/4波长的叠置薄储层,叠前时间偏移成像的垂向和空间分辨率低于常规处理结果。 相似文献
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Studies on the deactivations and initiations of gas phase polymerizations of 1,3‐butadiene have been achieved by Monte Carlo simulation. Initiation and deactivation control the reaction before and after the peak of the polymerization rate, respectively. The influence of polymerization temperature has been studied. Monte Carlo modeling of polymerization kinetics and mechanism was confirmed by the agreement of experimental data and simulation results of polymerizations run with a temporary evacuation of monomer. The balance of catalysts and active chains is established by both initiation and chain transfer reactions with cocatalyst, which causes a ‘pseudo‐stability’ stage. © 2003 Society of Chemical Industry 相似文献
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We consider the effect of multiple fibers on wavelength division multiplexing networks without wavelength conversion. We study networks with dynamic wavelength routing and develop accurate analytical models to compare various possible options using single- and multiple-fiber networks. We use results of an analytical model and simulation-based studies to evaluate the blocking performance and cost of multifiber networks. The number of fibers required providing high performance in multifiber networks and their costs are compared. A case is made for using multiple fibers in each link with fewer wavelengths instead of using a single fiber with many wavelengths. In particular, we show that a network with four fibers per link and with four wavelengths on each fiber without any wavelength conversion on any node yields similar same performance as the networks with one fiber per link and 16 wavelengths per fiber on each link and with full wavelength conversion capability on all nodes. In addition, the multifiber network may also offer the cost advantage depending on the relative cost of components. We develop a parametric cost model to show that multiple fibers in each link are an attractive option. Finally, such multifiber networks also has fault tolerance, with respect to a single fiber failure, already built into the system. 相似文献