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ACS Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/28626533/synthesis-and-anti-hcv-activity-of-a-novel-2-3-dideoxy-2-%C3%AE-fluoro-2-%C3%AE-c-methyl-guanosine-phosphoramidate-prodrug
#1
Wenquan Yu, Ertong Li, Zhigang Lv, Ke Liu, Xiaohe Guo, Yuan Liu, Junbiao Chang
A novel 2',3'-dideoxy-2'-α-fluoro-2'-β-C-methyl-6-methoxy guanosine (8) and its phosphoramidate prodrug (1) have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 μM) in the Huh-7 cell line. The prodrug (1) displayed nanomolar level antiviral activity (EC50 = 0.39-1.1 μM) against the HCV genotype (GT) 1a, 1b, 2a, and 1b S282T replicons.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626532/development-of-quinazoline-pyrimidine-2-4-1h-3h-diones-as-agonists-of-cannabinoid-receptor-type-2
#2
Hai-Yan Qian, Zhi-Long Wang, You-Lu Pan, Li-Li Chen, Xin Xie, Jian-Zhong Chen
Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626531/saccharin-aza-bioisosteres-synthesis-and-preclinical-property-comparisons
#3
Yantao Chen, Carl-Johan Aurell, Anna Pettersen, Richard J Lewis, Martin A Hayes, Matti Lepistö, Anna C Jonson, Hanna Leek, Linda Thunberg
Saccharin is a well-known scaffold in drug discovery. Herein, we report the synthesis and preclinical property comparisons of three bioisosteres of saccharin: aza-pseudosaccharins (cluster B), and two new types of aza-saccharins (clusters C and D). We demonstrate a convenient protocol to selectively synthesize products in cluster C or D when primary amines are used. Preclinical characterization of selected matched-pair products is reported. Through comparison of two diastereomers, we highlight how stereochemistry affects the preclinical properties...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626530/discovery-of-a-series-of-indazole-trpa1-antagonists
#4
David C Pryde, Brian E Marron, Christopher W West, Steven Reister, George Amato, Katrina Yoger, Brett Antonio, Karen Padilla, Peter J Cox, Jamie Turner, Joseph S Warmus, Nigel A Swain, Kiyoyuki Omoto, John H Mahoney, Aaron C Gerlach
A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed significant activity in these models when administered either systemically or topically. Protein chimeras were constructed to indicate compounds from the series bound in the S5 region of the channel, and a computational docking model was used to propose a binding mode for example compounds...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626529/photoaffinity-labeling-of-the-human-a2a-adenosine-receptor-and-cross-link-position-analysis-by-mass-spectrometry
#5
Hideyuki Muranaka, Takaki Momose, Chiaki Handa, Tomonaga Ozawa
Photoaffinity labeling (PAL) is widely used for the identification of ligand-binding proteins and elucidation of ligand-binding sites. PAL has also been employed for the characterization of G protein-coupled receptors (GPCRs); however, a limited number of reports has successfully identified their cross-linked amino acids. This report is the first of its kind to determine the cross-link position of the human A2A adenosine receptor by PAL with the novel diazirine-based photoaffinity probe 9.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626528/exploitation-of-conformational-dynamics-in-imparting-selective-inhibition-for-related-matrix-metalloproteinases
#6
Kiran V Mahasenan, Maria Bastian, Ming Gao, Emma Frost, Derong Ding, Katerina Zorina-Lichtenwalter, John Jacobs, Mark A Suckow, Valerie A Schroeder, William R Wolter, Mayland Chang, Shahriar Mobashery
Matrix metalloproteinases (MMPs) have numerous physiological functions and share a highly similar catalytic domain. Differential dynamical information on the closely related human MMP-8, -13, and -14 was integrated onto the benzoxazinone molecular template. An in silico library of 28,099 benzoxazinones was generated and evaluated in the context of the molecular-dynamics information. This led to experimental evaluation of 19 synthesized compounds and identification of selective inhibitors, which have potential utility in delineating the physiological functions of MMPs...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626527/systematic-data-mining-reveals-synergistic-h3r-mchr1-ligands
#7
David Schaller, Stefanie Hagenow, Gina Alpert, Alexandra Naß, Robert Schulz, Marcel Bermudez, Holger Stark, Gerhard Wolber
In this study, we report a ligand-centric data mining approach that guided the identification of suitable target profiles for treating obesity. The newly developed method is based on identifying target pairs for synergistic positive effects and also encompasses the exclusion of compounds showing a detrimental effect on obesity treatment (off-targets). Ligands with known activity against obesity-relevant targets were compared using fingerprint representations. Similar compounds with activities to different targets were evaluated for the mechanism of action since activation or deactivation of drug targets determines the pharmacological effect...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626526/efficient-divergent-synthesis-of-new-immunostimulant-4%C3%A2-modified-%C3%AE-galactosylceramide-analogues
#8
Jonas Janssens, Tine Decruy, Koen Venken, Toshiyuki Seki, Simon Krols, Johan Van der Eycken, Moriya Tsuji, Dirk Elewaut, Serge Van Calenbergh
A synthesis strategy for the swift generation of 4″-modified α-galactosylceramide (α-GalCer) analogues is described, establishing a chemical platform to comprehensively investigate the structure-activity relationships (SAR) of this understudied glycolipid part. The strategy relies on a late-stage reductive ring-opening of a p-methoxybenzylidene (PMP) acetal to regioselectively liberate the 4″-OH position. The expediency of this methodology is demonstrated by the synthesis of a small yet diverse set of analogues, which were tested for their ability to stimulate invariant natural killer T-cells (iNKT) in vitro and in vivo...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626525/identification-of-better-pharmacokinetic-benzothiazinone-derivatives-as-new-antitubercular-agents
#9
Kai Lv, Xuefu You, Bin Wang, Zengquan Wei, Yun Chai, Bo Wang, Apeng Wang, Guocheng Huang, Mingliang Liu, Yu Lu
A series of new 8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one(BTZ) derivatives containing a C-2 nitrogen spiro-heterocycle moiety based on the structures of BTZ candidates BTZ043 and PBTZ169 were designed and synthesized as new antitubercular agents. Many of them were found to have excellent in vitro activity (MIC < 0.15 μM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains. Compounds 11l and 11m display acceptable safety, greater aqueous solubility, and better pharmacokinetic profiles than PBTZ169, suggesting their promising potential to be lead compounds for future antitubercular drug discovery...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626524/-19-f-nmr-based-dual-site-reporter-assay-for-the-discovery-and-distinction-of-catalytic-and-allosteric-kinase-inhibitors
#10
Lukasz Skora, Wolfgang Jahnke
In modern kinase drug discovery, allosteric inhibitors have become a focus of attention due to their potential selectivity, but such compounds are difficult to identify. Here we describe an NMR-based competition assay using (19)F-containing reporter molecules, which allows for rapid identification and discrimination between ATP-competitive and allosteric kinase inhibitors. We illustrate the principle of such a dual-site competition assay with the example of catalytic and allosteric ABL1 kinase inhibitors. The assay can also be used to identify and characterize mixed binding modes of well-known drugs, as shown for crizotinib and fingolimod...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626523/antiobesity-effect-of-a-short-length-peptide-yy-analogue-after-continuous-administration-in-mice
#11
Naoki Nishizawa, Ayumu Niida, Yasushi Masuda, Satoshi Kumano, Kotaro Yokoyama, Hideki Hirabayashi, Nobuyuki Amano, Tetsuya Ohtaki, Taiji Asami
Gastrointestinal peptides such as peptide YY (PYY) can regulate appetite, which is relevant to the study of obesity. The intraperitoneal bolus administration of PYY3-36 and a 12-amino acid PYY analogue, benzoyl-[Cha(27,28,36),Aib(31)]PYY25-36 (1), showed similar anorectic activity by activating the Y2 receptor (Y2R). However, food intake inhibition and body weight loss were not observed upon continuous subcutaneous administration of 1 with osmotic pumps in diet-induced obese (DIO) mice. N-Terminal elongation of 1, together with amino acid substitution at position 24, led to a hydrophilic 14-amino acid peptide, Ac-[d-Hyp(24),Cha(27,28,36),Aib(31)]PYY23-36 (18), that showed higher affinity and more potent agonist activity for Y2R and a robust anorectic activity with potency similar to that of PYY3-36...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626522/study-of-para-quinone-methide-precursors-toward-the-realkylation-of-aged-acetylcholinesterase
#12
Ryan J Yoder, Qinggeng Zhuang, Jeremy M Beck, Andrew Franjesevic, Travis G Blanton, Sydney Sillart, Tyler Secor, Leah Guerra, Jason D Brown, Carolyn Reid, Craig A McElroy, Özlem Doğan Ekici, Christopher S Callam, Christopher M Hadad
Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP-AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626521/identification-and-characterization-of-jak2-pseudokinase-domain-small-molecule-binders
#13
David E Puleo, Kaury Kucera, Henrik M Hammarén, Daniela Ungureanu, Ana S Newton, Olli Silvennoinen, William L Jorgensen, Joseph Schlessinger
Janus kinases (JAKs) regulate hematopoiesis via the cytokine-mediated JAK-STAT signaling pathway. JAKs contain tandem C-terminal pseudokinase (JH2) and tyrosine kinase (JH1) domains. The JAK2 pseudokinase domain adopts a protein kinase fold and, despite its pseudokinase designation, binds ATP with micromolar affinity. Recent evidence shows that displacing ATP from the JAK2 JH2 domain alters the hyperactivation state of the oncogenic JAK2 V617F protein while sparing the wild type JAK2 protein. In this study, small molecule binders of JAK2 JH2 were identified via an in vitro screen...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626520/jak2-jh2-fluorescence-polarization-assay-and-crystal-structures-for-complexes-with-three-small-molecules
#14
Ana S Newton, Luca Deiana, David E Puleo, José A Cisneros, Kara J Cutrona, Joseph Schlessinger, William L Jorgensen
A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as Kd results for 10 compounds, including JNJ7706621, NVP-BSK805, and filgotinib (GLPG0634). X-ray crystal structures of JAK2 JH2 in complex with NVP-BSK805, filgotinib, and diaminopyrimidine 8 elucidate the binding poses.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626519/discovery-of-potent-and-selective-tricyclic-inhibitors-of-bruton-s-tyrosine-kinase-with-improved-druglike-properties
#15
Xiaojing Wang, James Barbosa, Peter Blomgren, Meire C Bremer, Jacob Chen, James J Crawford, Wei Deng, Liming Dong, Charles Eigenbrot, Steve Gallion, Jonathon Hau, Huiyong Hu, Adam R Johnson, Arna Katewa, Jeffrey E Kropf, Seung H Lee, Lichuan Liu, Joseph W Lubach, Jen Macaluso, Pat Maciejewski, Scott A Mitchell, Daniel F Ortwine, Julie DiPaolo, Karin Reif, Heleen Scheerens, Aaron Schmitt, Harvey Wong, Jin-Ming Xiong, Jianjun Xu, Zhongdong Zhao, Fusheng Zhou, Kevin S Currie, Wendy B Young
In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626518/practical-high-throughput-experimentation-for-chemists
#16
Michael Shevlin
Large arrays of hypothesis-driven, rationally designed experiments are powerful tools for solving complex chemical problems. Conceptual and practical aspects of chemical high-throughput experimentation are discussed. A case study in the application of high-throughput experimentation to a key synthetic step in a drug discovery program and subsequent optimization for the first large scale synthesis of a drug candidate is exemplified.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626517/janus-associated-kinase-1-jak1-inhibitors-as-potential-treatment-for-immune-disorders
#17
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626516/inhibitors-of-adaptor-associated-kinase-1-aak1-may-treat-neuropathic-pain-schizophrenia-parkinson-s-disease-and-other-disorders
#18
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626515/inhibitors-of-dna-gyrase-gyrb-subunit-and-or-topoisomerase-iv-pare-subunit-may-treat-infectious-diseases-caused-by-antibiotic-resistant-bacteria
#19
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626514/where-are-drugs-invented-and-why-does-it-matter
#20
EDITORIAL
Yali Friedman
Globalization has disrupted many industries, initially shifting unskilled labor employment from high wage-cost industrialized nations to lower wage-cost emerging economies. There has been a trend toward moving increasingly skilled work away from industrialized nations, which raises the question-has innovative research and development been affected by globalization, and why is relocation of innovation much more than a simple economic concern?
June 8, 2017: ACS Medicinal Chemistry Letters
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