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171.
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
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Grundwasser - Chloridazon ist ein Herbizidwirkstoff, der in Deutschland seit 1964 für den Einsatz in der Landwirtschaft zugelassen ist. Er wird hauptsächlich beim Anbau von Rüben,... 相似文献
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Christoph Schmerbauch Jesus Gonzalez‐Julian Robert Röder Carsten Ronning Olivier Guillon 《Journal of the American Ceramic Society》2014,97(6):1728-1735
We report the sintering behavior of nanocrystalline zinc oxide under external AC electric field between 0 and 160 V/cm. In situ acquisition of density by means of laser dilatometry, evaluation of specimen temperature, real‐time measurement of electric field and current help analyze this peculiar behavior. Field strength and blocking electrodes significantly affect densification and microstructure, which was evaluated in the vicinity of the flash event and for the fully sintered material. High current densities flow through the sample at high electric fields, entailing a sudden increment of the temperature estimated to several hundreds of K and an exaggerated grain growth. In contrast, low current density flows through the sample at lower electric fields, which guarantees normal grain growth and highest final density. Macroscopic photoluminescence measurements give insights into the development of the defect structure. Electric fields are expected to enhance defect mobility, explaining the high densification rates observed during the sintering process. 相似文献
178.
Ammoniaksynthese als Beispiel einer stofflichen Nutzung von intermittierend erzeugtem Wasserstoff
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Simon Schulte Beerbühl Dr. Bärbel Kolbe Dr. Christoph Roosen Prof. Dr. Frank Schultmann 《化学,工程师,技术》2014,86(5):649-657
Producing hydrogen‐rich chemicals, such as methane, ammonia or methanol, from renewable energy may foster the integration of renewables into the current energy system. Here, a flexible ammonia synthesis concept is introduced, which is then compared to the widely discussed power‐to‐gas concepts on a technical and economic level. The current ammonia prices result in comparably high hydrogen‐specific revenues, which imply the ability to operate the system more profitable under fluctuating electricity prices and thereby increase the plant capacity factor. 相似文献
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We present a method for mapping the spatial distribution of viscoelastic properties of heterogeneous samples using the atomic force microscope (AFM). By applying a force step load protocol to induce time dependent sample indentations we measured the local creep compliance of the sample. The creep compliance was quantified in terms of the standard linear solid model to give maps of the instant glassy modulus, the equilibrium rubbery modulus, and the retardation time. To reduce the influence of plastic deformations, the sample was preformed with an initial preload step. Different polymer samples with a homogeneous or a heterogeneous material composition on a microscopic scale were investigated. 相似文献
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Conformationally disordered α′-crystals of poly (l-lactic acid) were formed by crystallization of the melt at high supercooling at 95 °C. Analysis of their melting temperature as a function of the crystallinity revealed absence of crystal thickening during isothermal crystallization. Annealing of α′-crystals between the crystallization temperature of 95 °C and their zero-entropy production melting temperature of 150 °C leads to their stabilization, mainly by solid-state reorganization. Heating faster than 30 K s−1 suppresses reorganization and permits superheating of the α′-phase. Consequently, isothermal melting followed by melt-recrystallization becomes accessible. Melting is completed within few hundreds of milliseconds, and melt-recrystallization is about two orders of magnitude faster than crystallization of the isotropic melt at identical temperature. The time required for melting decreases with superheating and increases with the lateral dimension of the lamellar crystals. Laterally extended lamellae require long time for melting of the outer crystal layers, which allows stabilization of the central crystal part. These crystal remnants then serve as seed for immediate recrystallization. In case of complete melting of smaller lamellae, melt-recrystallization is retarded but still distinctly faster than cold- and melt-crystallization, due to incomplete isotropization of the melt. 相似文献