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John T Randolph, Charles A Flentge, Pamela Donner, Todd W Rockway, Sachin V Patel, Lissa Nelson, Douglas K Hutchinson, Rubina Mondal, Neeta Mistry, Thomas Reisch, Tatyana Dekhtyar, Preethi Krishnan, Tami Pilot-Matias, Deanne F Stolarik, David W A Beno, Rolf Wagner, Clarence Maring, Warren M Kati
Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series...
October 13, 2016: Bioorganic & Medicinal Chemistry Letters
Simone A Winkler, Paul A Picot, Michael M Thornton, Brian K Rutt
PURPOSE: To develop a new method capable of directly measuring specific absorption rate (SAR) deposited in tissue using the thermoacoustic signal induced by short radiofrequency (RF) pulse excitation. THEORY: A detailed model based on the thermoacoustic wave generation and propagation is presented. METHODS: We propose a new concept for direct measurement of SAR, to be used as a safety assessment/monitoring tool for MRI. The concept involves the use of short bursts of RF energy and the measurement of the resulting thermoacoustic excitation pattern by an array of ultrasound transducers, followed by image reconstruction to yield the 3D SAR distribution...
October 25, 2016: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
Igor V Tetko, Uko Maran, Alexander Tropsha
Thousands of (Quantitative) Structure-Activity Relationships (Q)SAR models have been described in peer-reviewed publications; however, this way of sharing seldom makes models available for the use by the research community outside of the developer's laboratory. Conversely, on-line models allow broad dissemination and application representing the most effective way of sharing the scientific knowledge. Approaches for sharing and providing on-line access to models range from web services created by individual users and laboratories to integrated modeling environments and model repositories...
October 25, 2016: Molecular Informatics
Barry C Jones, Helen Rollison, Susanne A Johansson, Kajsa P Kanebratt, Craig Lambert, Karthick Vishwanathan, Tommy B Andersson
Induction of cytochrome P450 (CYP) can impact the efficacy and safety of a drug molecule upon multiple dosing of co-administered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of CYP induction are related to this enzyme. However, the in vitro evaluation of induction is applicable to other CYP enzymes but the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the pre-clinical phase, compounds are screened using PXR reporter gene assay and, if necessary, structure-activity relationships (SAR) are developed...
October 24, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Min Wang, Shan Xu, Chunjiang Wu, Xiaobo Liu, Hong Tao, Yanli Huang, Yongchan Liu, Pengwu Zheng, Wufu Zhu
Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a-o, 7a-e) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC50 values of 0...
October 12, 2016: Bioorganic & Medicinal Chemistry Letters
Daniele Giordan, Paolo Allasia, Niccolò Dematteis, Federico Dell'Anese, Marco Vagliasindi, Elena Motta
In this work, we present the results of a low-cost optical monitoring station designed for monitoring the kinematics of glaciers in an Alpine environment. We developed a complete hardware/software data acquisition and processing chain that automatically acquires, stores and co-registers images. The system was installed in September 2013 to monitor the evolution of the Planpincieux glacier, within the open-air laboratory of the Grandes Jorasses, Mont Blanc massif (NW Italy), and collected data with an hourly frequency...
October 21, 2016: Sensors
Violina Angelova, Valentin Karabeliov, Pavlina A Andreeva-Gateva, Jana Tchekalarova
Preclinical Research Epilepsy is a chronic devastating neurological disorder characterized by synchronous interictal discharges. Treatment with antiepileptic drugs (AEDs) can alleviate spontaneous seizure activity without preventing the progression and development of epileptogenesis. Current design and development of new AEDs and strategies for the prevention of epilepsy is focused mainly on attenuating uncontrolled seizures, severe side effects and toxicity in chronic drug therapy. It has thus become necessary to discover new chemical pharmacophores with a broad spectrum of activity and less neurotoxicity...
October 24, 2016: Drug Development Research
Vincent Gras, Alexandre Vignaud, Alexis Amadon, Franck Mauconduit, Denis Le Bihan, Nicolas Boulant
PURPOSE: A multispoke specific absorption rate (SAR) -aware pulse design approach for homogeneous multiple-slice small and large flip angle (FA) excitations with parallel transmission is proposed. The approach aims at optimizing in a slice-specific manner the spokes locations and radiofrequency pulses. METHODS: The problem is posed as a set of slice-specific magnitude-least-squares problems, linked together by hardware and SAR constraints, and solved jointly using an active-set algorithm...
October 23, 2016: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
I R MacDonald, O Garcia-Pineda, A Beet, S Daneshgar Asl, L Feng, G Graettinger, D French-McCay, J Holmes, C Hu, F Huffer, I Leifer, F Muller-Karger, A Solow, M Silva, G Swayze
When wind speeds are 2-10 m s(-1), reflective contrasts in the ocean surface make oil slicks visible to synthetic aperture radar (SAR) under all sky conditions. Neural network analysis of satellite SAR images quantified the magnitude and distribution of surface oil in the Gulf of Mexico from persistent, natural seeps and from the Deepwater Horizon (DWH) discharge. This analysis identified 914 natural oil seep zones across the entire Gulf of Mexico in pre-2010 data. Their ∼0.1 µm slicks covered an aggregated average of 775 km(2)...
December 2015: Journal of Geophysical Research. Oceans
Satoru Noji, Noriyoshi Seki, Takaki Maeba, Takayuki Sakai, Eiichi Watanabe, Katsuya Maeda, Kyoko Fukushima, Toru Noguchi, Kazuya Ogawa, Yukiyo Toyonaga, Tamotsu Negoro, Hisashi Kawasaki, Makoto Shiozaki
In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy...
October 13, 2016: ACS Medicinal Chemistry Letters
Nilgun Isik Reed, You-Zhi Tang, Joel McIntosh, Yibing Wu, Kathleen S Molnar, Annafelicia Civitavecchia, Dean Sheppard, William F DeGrado, Hyunil Jo
One small molecule inhibitor of αvβ1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure-activity relationships (SAR) in αvβ1 integrin inhibition. N-Phenylsulfonyl-l-homoproline analogues of c8 maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished...
October 13, 2016: ACS Medicinal Chemistry Letters
Yazhou Wang, Wei Huang, Minhang Xin, Pan Chen, Li Gui, Xinge Zhao, Feng Tang, Jia Wang, Fei Liu
Janus kinases inhibitor is considered to have therapeutic potential for the treatment of oncology and immune-inflammatory diseases. Two series of 4-(2-benzofuranyl)pyrimidin-2-amine and 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)pyrimidin-2-amine derivatives have been designed and synthesized. Primary SAR studies resulted in the discovery of a novel class of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine based JAK2 inhibitors with higher potency (IC50 of 0.7nM) and selectivity (>30 fold) to JAK3 kinase than tofacitinib...
October 11, 2016: Bioorganic & Medicinal Chemistry
Shan Qian, Tao He, Wei Wang, Yanying He, Man Zhang, Lingling Yang, Guobo Li, Zhouyu Wang
Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5...
October 6, 2016: Bioorganic & Medicinal Chemistry
Jie Gao, Narasimha Midde, Jun Zhu, Alvin V Terry, Campbell McInnes, James M Chapman
Using molecular modeling and rationally designed structural modifications, the multi-target structure-activity relationship for a series of ranitidine analogs has been investigated. Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties provide optimal interactions with the hydrophobic and π-π interactions with the peripheral anionic site of the AChE active site. The SAR of a series of cyclic imides demonstrated that AChE inhibition is increased by additional aromatic rings, where 1,8-naphthalimide derivatives were the most potent analogs and other key determinants were revealed...
October 6, 2016: Bioorganic & Medicinal Chemistry Letters
Shuai Wang, Li-Jie Zhao, Yi-Chao Zheng, Dan-Dan Shen, Er-Fei Miao, Xue-Peng Qiao, Li-Juan Zhao, Ying Liu, Ruilei Huang, Bin Yu, Hong-Min Liu
A new series of [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1 inhibitors were designed, synthesized, and further evaluated for their cytotoxicity against MGC-803, EC109, A549 and PC-9 cells as well as the ability of inhibiting LSD1. Some of these compounds showed potent inhibition toward LSD1 and selectively inhibited growth of A549 and PC-9 cells. Compound 6l potently inhibited growth of PC-9 cells (IC50 = 0.59 μM), about 4-fold more potent than 5-FU. Further SARs studies led to the identification of compounds 6l-m, which had good growth inhibition against all the tested cancer cell lines and were much more potent than 5-FU and GSK2879552...
October 14, 2016: European Journal of Medicinal Chemistry
Yanyan Zheng, Li Zhu, Lulu Fan, Wenna Zhao, Jianlong Wang, Xianxiao Hao, Yunhui Zhu, Xiufang Hu, Yaofeng Yuan, Jingwei Shao, Wenfeng Wang
Emodin, a natural anthraquinone derivative isolated from Rheum palmatum L., has been demonstrated to exhibit good anti-cancer effect. In this study, a series of novel quaternary ammonium salts of emodin, anthraquinone and anthrone were synthesized and their anticancer activities were tested in vitro. The effects of emodin quaternary ammonium salts on cell viability, apoptosis, intracellular ROS, and mitochondrial membrane potential were investigated in A375, BGC-823, HepG2 and HELF cells. The results demonstrated that compound 4a induced morphological changes and decreased cell viability...
October 7, 2016: European Journal of Medicinal Chemistry
Xing-Hai Liu, Wen Zhao, Zhong-Hua Shen, Jia-Hua Xing, Tian-Ming Xu, Wei-Li Peng
A series of novel difluoromethylpyrazole carboxamides derivatives were synthesized by introduction of flexible alkyl chain. Nematicidal bioassay results showed that some of them exhibited good control efficacy against M. incognita, which indicated that these difluoromethylpyrazole carboxamides derivatives might be potential novel lead compounds for discovery new nematicides. The nematicidal activity was affected by the substituted position in the molecule, especially the substitution group on the alkyl chain...
October 10, 2016: European Journal of Medicinal Chemistry
Ann M Buysse, Maurice C H Yap, Ricky Hunter, Jonathan Babcock, Xinpei Huang, Marshall H Parker
BACKGROUND: Optimization studies on compounds initially designed to be herbicides led to the discovery of a series of [6-(3-pyridyl)pyridazin-3-yl]amides exhibiting aphicidal properties. Systematic modifications of the amide moiety as well as the pyridine and pyridazine rings were carried out to determine if these changes could improve insecticidal potency. RESULTS: Structure-activity relationship (SAR) studies showed that changes to the pyridine and pyridazine rings generally resulted in a significant loss of insecticidal potency against green peach aphids (Myzus persicae (Sulzer) and cotton aphids (Aphis gossypii (Glover)...
October 21, 2016: Pest Management Science
Nima Sarli, Tracy Marien, Christopher R Mitchell, Giuseppe Del Giudice, Mary S Dietrich, S Duke Herrell, Nabil Simaan
BACKGROUND: Transurethral Resection of Bladder Tumors (TURBT) is a challenging procedure partly due to resectoscope limitations. To date, manual resection performance has not been fully characterized. This work characterizes manual resection performance in the bladder while analyzing the effect of resection location on accuracy. METHODS: Kinematic simulations are used to assess kinematic measures of resection dexterity. An experimental protocol for manual resection accuracy assessment is developed...
October 20, 2016: International Journal of Medical Robotics + Computer Assisted Surgery: MRCAS
Ewa Szymańska, Paulina Chałupnik, Katarzyna Szczepańska, Ana Maria Cuñado Moral, Darryl S Pickering, Birgitte Nielsen, Tommy N Johansen, Katarzyna Kieć-Kononowicz
A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1-GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (Ki values in the range of 4.9-7.5μM). A structure-activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established...
September 30, 2016: Bioorganic & Medicinal Chemistry Letters
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