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1.
Dr. Christine Brotschi Dr. Martin H. Bolli Dr. John Gatfield Dr. Bibia Heidmann Dr. Francois Jenck Dr. Catherine Roch Dr. Thierry Sifferlen Dr. Alexander Treiber Dr. Jodi T. Williams Dr. Christoph Boss 《ChemMedChem》2020,15(5):430-448
The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone ( 6 ), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 . 相似文献
2.
Nano design for macroscopic coatings – new application potentials by PVD coatings up to 100 μm thickness Non-homogeneous coatings still limit the application of thicker layers due to defect growth and irregular layer thickness distribution along the surface of complex shaped components. Therefore, the layer thickness is usually limited to about 10 μm. In order to limit the surface roughness by the growing layer, multilayer coating systems are deposited by highly ionized plasmas. This allows significantly smoother layers to be produced, which until now could only be produced by mechanical finishing. Furthermore, by combining selected material systems and targeted parameter selection, structures can be deposited during coating, especially on edges, which result in a reduction of the cutting edge radius. In future, edge geometries should therefore be able to be specifically adjusted through the coating process. 相似文献
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Adrian Caspari Christoph Offermanns Pascal Schäfer Adel Mhamdi Alexander Mitsos 《American Institute of Chemical Engineers》2019,65(11):e16705
The flexible operation of energy-intensive processes, such as cryogenic air separation, has economic potential due to increasing fluctuations of the electricity markets. Multiproduct air separation processes with high ratios of liquid product are very promising for flexible operation due to storable products. We present a process design with an integrated liquefication cycle and liquid assist operation, that facilitates a high liquid product ratio and a flexible process operation. We use a mechanistic dynamic process model in steady-state process optimizations covering the wide operational range of the proposed process. The optimization results show that the power demand can be varied in a range from 3.5 to 28 MW without violating operational constraints by changing the nitrogen and oxygen production rates. Thus, the proposed process is a promising air separation candidate for flexible operation with respect to fluctuating electricity markets. 相似文献
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Tran Thi Ngoc Trang Felfernig Alexander Trattner Christoph Holzinger Andreas 《Journal of Intelligent Information Systems》2021,57(1):171-201
Journal of Intelligent Information Systems - Nowadays, a vast amount of clinical data scattered across different sites on the Internet hinders users from finding helpful information for their... 相似文献
7.
In the course of classical optics manufacturing glass components are in permanent direct contact with aqueous operating materials. Such contact leads to a certain absorption of water and hydrogenous compounds that may induce severe glass defects. In this contribution, absorption of hydrogen and other contaminants during grinding of glass was observed and qualitatively detected via laser‐induced breakdown spectroscopy. It is shown that hydrogen, calcium, magnesium, and carbon are implanted into the glass surface where the contaminant concentration increases over grinding time or contact time of the glass surface with water and the grinding tool, respectively. The contaminants hydrogen, calcium, and magnesium can be attributed to the water used as lubricant. In contrast, carbon most likely originates from wear debris of the used silicon carbide grinding pads. Several possible mechanisms that lead to such surface contamination of glasses during grinding – diffusion, accumulation in micro cracks as well as the formation of hydrated silica – are finally introduced. 相似文献
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Shrikrishnan Sankaran Judith Becker Christoph Wittmann Arnzazu del Campo 《Small (Weinheim an der Bergstrasse, Germany)》2019,15(5)
On‐demand and long‐term delivery of drugs are common requirements in many therapeutic applications, not easy to be solved with available smart polymers for drug encapsulation. This work presents a fundamentally different concept to address such scenarios using a self‐replenishing and optogenetically controlled living material. It consists of a hydrogel containing an active endotoxin‐free Escherichia coli strain. The bacteria are metabolically and optogenetically engineered to secrete the antimicrobial and antitumoral drug deoxyviolacein in a light‐regulated manner. The permeable hydrogel matrix sustains a viable and functional bacterial population and permits diffusion and delivery of the synthesized drug to the surrounding medium at quantities regulated by light dose. Using a focused light beam, the site for synthesis and delivery of the drug can be freely defined. The living material is shown to maintain considerable levels of drug production and release for at least 42 days. These results prove the potential and flexibility that living materials containing engineered bacteria can offer for advanced therapeutic applications. 相似文献
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Dr. Wojciech Schönemann Dr. Jonathan Cramer Tobias Mühlethaler Dr. Brigitte Fiege Marleen Silbermann Dr. Said Rabbani Dr. Philipp Dätwyler Dr. Pascal Zihlmann Dr. Roman P. Jakob Dr. Christoph P. Sager Dr. Martin Smieško Dr. Oliver Schwardt Prof. Dr. Timm Maier Prof. Dr. Beat Ernst 《ChemMedChem》2019,14(7):749-757
Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d -mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar KD values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as 1H,15N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability. 相似文献