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191.
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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Dr. Gabriel E. Büchel Brandon Carney Travis M. Shaffer Dr. Jun Tang Dr. Christine Austin Prof. Manish Arora Prof. Brian M. Zeglis Prof. Jan Grimm Prof. Jörg Eppinger Prof. Thomas Reiner 《ChemMedChem》2016,11(18):1978-1982
Intraoperative imaging technologies recently entered the operating room, and their implementation is revolutionizing how physicians plan, monitor, and perform surgical interventions. In this work, we present a novel surgical imaging reporter system: intraoperative chemiluminescence imaging (ICI). To this end, we have leveraged the ability of a chemiluminescent metal complex to generate near‐infrared light upon exposure to an aqueous solution of Ce4+ in the presence of reducing tissue or blood components. An optical camera spatially resolves the resulting photon flux. We describe the construction and application of a prototype imaging setup, which achieves a detection limit as low as 6.9 pmol cm?2 of the transition‐metal‐based ICI agent. As a proof of concept, we use ICI for the in vivo detection of our transition metal tracer following both systemic and subdermal injections. The very high signal‐to‐noise ratios make ICI an interesting candidate for the development of new intraoperative imaging technologies. 相似文献
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Buchner Daniel Schweikhart Meenakshi Behrens Sebastian Schöndorf Thomas Laskov Christine Haderlein Stefan B. 《Grundwasser》2019,24(1):51-63
Grundwasser - Eine erfolgreiche biologische In-situ-Sanierung von PCE-kontaminierten Grundwasserleitern erfordert hinreichend reduzierende Bedingungen sowie die Anwesenheit von molekularem... 相似文献
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Oxidation of Metals - A straightforward conceptual tool for discriminating between different oxide scaling processes deviating from the parabolic standard model is formulated. Grain boundary... 相似文献
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Christine Bressy Claire Hellio Minh Ngoc Nguyen Brigitte Tanguy Jean-Philippe Maréchal André Margaillan 《Progress in Organic Coatings》2014
This work focuses on the assessment of the erosion properties and antifouling (AF) performance of silyl ester copolymer-based coatings through laboratory and field tests. Silyl ester diblock copolymers were synthesized via the reversible addition-fragmentation chain transfer polymerization and were selected as binders for developing copper-free chemically active coatings. AF coatings were subsequently prepared using biocides (Sea-Nine™ 211, Preventol® A4S, and zinc pyrithione). Laboratory-based bioassays, targeting the growth of selected microorganisms (bacteria and microalgae) and barnacle settlement, highlighted that the silyl ester methacrylic-based binders did not inhibit the growth of microorganisms, are essentially non-toxic to nauplii and reduced the settlement of Amphibalanus amphitrite cyprids. The corresponding biocidal coatings are potent toward bacteria and diatoms but were demonstrated to be toxic against the barnacle larvae. Field test results showed variations with geographical locations: in sub-tropical area, the silyl ester methacrylic-based coatings failed to inhibit the settlement of barnacles; however, field tests performed in Mediterranean Sea for 18 months demonstrated that biocidal silyl ester methacrylic-based coatings were promising candidates. 相似文献
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正Ground control is the science of studying and controlling the behavior of rock strata in response to mining operations.Ground-control-related research has seen significant advancements over the last 40 years, and these accomplishments are well documented in the proceedings of the annual International Conference on Ground Control in Mining (ICGCM)[1]. 相似文献