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Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/28107633/binding-and-proton-blockage-by-amantadine-variants-of-the-influenza-m2wt-and-m2s31n-explained
#1
Christina Tzitzoglaki, Anna K Wright, Kathrin-Maria Freudenberger, Anja Hoffmann, Ian Tietjen, Ioannis Stylianakis, Felix Kolarov, David Fedida, Michaela Schmidtke, Guenter Gauglitz, Timothy A Cross, Antonios Kolocouris
While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, anti-viral assays and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M2S31N. This is due to reshaping of the M2pore when N31 is present, which in contrast to WT, leads: A) to the loss of the V27 pocket for the adamantyl cage and to a predominant orientation of the ligand's ammonium group toward the N-terminus and, B) to the lack of a helical kink upon ligand binding...
January 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28107629/discovery-of-1-2-3-triazole-derivatives-for-multimodality-pet-ct-cryoimaging-of-myelination-in-the-central-nervous-system
#2
Chunying Wu, Brendan Eck, Sheng Zhang, Junqing Zhu, Anand Dev Tiwari, Yifan Zhang, Yunjie Zhu, Jinming Zhang, Bin Wang, Xizhen Wang, Xu Wang, Jingqiang You, Jian Wang, Yihui Guan, Xingdang Liu, Xin Yu, Bruce D Trapp, Robert Miller, Jerry Silver, David Wilson, Yanming Wang
Myelin pathology is present in many neurological conditions such as multiple sclerosis (MS) and traumatic spinal cord injury (SCI). To facilitate development of novel therapies aimed at myelin repair, we set out to develop imaging agents that permit direct quantification of myelination in vivo. In this work, we designed and synthesized a series of fluorescent fluorinated myelin imaging agents that can be used for in vivo positron emission tomography (PET) imaging combined with subsequent post-mortem fluorescent cryoimaging...
January 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28106992/discovery-of-n-pyridin-4-yl-1-5-naphthyridin-2-amines-as-potential-tau-pathology-pet-tracers-for-alzheimer-s-disease
#3
Frederik J R Rombouts, José-Ignacio Andrés, Manuela Ariza, José Manuel Alonso, Nigel Austin, Astrid Bottelbergs, Lu Chen, Vladimir Chupakhin, Erna Cleiren, Katleen Fierens, Alberto Fontana, Xavier Langlois, Joseph E Leenaerts, Jonas Mariën, Carolina Martinez Lamenca, Rhys Salter, Mark E Schmidt, Paula Te Riele, Cindy Wintmolders, Andrés A Trabanco, Wei Zhang, Gregor J Macdonald, Diederik Moechars
A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with sub-optimal physicochemical properties...
January 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28106991/discovery-of-a-phosphoinositide-3-kinase-pi3k-b-d-inhibitor-for-the-treatment-of-phosphatase-and-tensin-homolog-pten-deficient-tumors-building-pi3kb-potency-in-a-pi3kd-selective-template-by-targeting-non-conserved-asp856
#4
Stéphane Perreault, Jayaraman Chandrasekhar, Zhi-Hua Cui, Jerry B Evarts, Jia Hao, Joshua A Kaplan, Adam Kashishian, Kathleen S Keegan, Thomas Kenney, David J Koditek, Latesh Lad, Eve-Irene Lepist, Mary E McGrath, Leena Patel, Bart Phillips, Joseph Therrien, Jennifer Treiberg, Anella Yahiaoui, Gary Phillips
Phosphoinositide 3-kinase (PI3K) beta signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kbeta/delta inhibitors in which PI3Kbeta potency was built in a PI3Kdelta-selective template. This work led to the discovery of a highly selective PI3Kbeta/delta inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model...
January 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28051863/development-of-the-first-two-pore-domain-potassium-channel-twik-related-k-channel-1-selective-agonist-possessing-in-vivo-antinociceptive-activity
#5
Delphine Vivier, Ismail Ben Soussia, Nuno Rodrigues, Stéphane Lolignier, Maïly Devilliers, Franck C Chatelain, Laetitia Prival, Eric Chapuy, Geoffrey Bourdier, Khalil Bennis, Florian Lesage, Alain Eschalier, Jérôme Busserolles, Sylvie Ducki
The TWIK-related K(+) channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here, we report the synthesis of a series of substituted acrylic acids (1-54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced writhing and hot plate assays), leading to the identification of a series of novel molecules able to activate TREK-1 and displaying potent antinociceptive activity in vivo...
January 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28103033/design-synthesis-and-biological-evaluation-of-small-high-affinity-siglec-7-ligands-toward-novel-inhibitors-of-cancer-immune-evasion
#6
Horst Prescher, Martin Frank, Stephan Gütgemann, Elena Kuhfeldt, Astrid Schweizer, Lars Nitschke, Carsten Watzl, Reinhard Brossmer
Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion...
January 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28103025/identification-of-the-first-selective-activin-receptor-like-kinase-1-inhibitor-a-reversible-version-of-l-783277
#7
Hanna Cho, Sandip Sengupta, Sean Sh Jeon, Wooyoung Hur, Hwan Geun Choi, Hong Seog Seo, Byung Joo Lee, Jeong Hun Kim, Minhwan Chung, Noo Li Jeon, Nam Doo Kim, Taebo Sim
We synthesized 1 (San78-130), a reversible version of L-783277, as a selective and potent ALK1 inhibitor. Our study showed that 1 possesses great kinase selectivity against a panel of 342 kinases and more potent activity against ALK1 than L-783277. Among the six ALK isotypes (ALK1-6), ALK1 is most significantly inhibited by compound 1. Compound 1 suppresses the BMP9-induced Smad1/5 pathway by mainly inhibiting ALK1 in C2C12 cells. Our molecular dynamics simulations suggest that H-bonding interaction between the C-4' hydroxyl group of 1 and Arg334 of ALK1 substantially contributes to the ALK1 inhibition...
January 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28103022/discovery-of-a-novel-series-of-orally-bioavailable-and-cns-penetrant-glucagon-like-peptide-1-receptor-glp-1r-non-competitive-antagonists-based-on-a-1-3-disubstituted-7-aryl-5-5-bis-trifluoromethyl-5-8-dihydropyrimido-4-5-d-pyrimidine-2-4-1h-3h-dione-core
#8
Kellie D Nance, Emily L Days, C David Weaver, Anastasia Coldren, Tiffany D Farmer, Hyekyung P Cho, Colleen M Niswender, Anna L Blobaum, Kevin D Niswender, Craig W Lindsley
A duplexed, functional multi-addition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon-like peptide-1 receptor (GLP-1R) non-competitive antagonist. Antagonist 5d not only blocked Exendin-4-stimulated insulin release in islets, but also lowered insulin levels while increasing blood glucose in vivo.
January 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28072531/discovery-of-2-1r-4r-4-4-chlorophenyl-phenyl-carbamoyl-oxy-methyl-cyclohexyl-methoxy-acetate-ralinepag-an-orally-active-prostacyclin-receptor-agonist-for-the-treatment-of-pulmonary-arterial-hypertension
#9
Thuy-Anh Tran, Bryan Kramer, Young-Jun Shin, Pureza Vallar, P Douglas Boatman, Ning Zou, Carleton R Sage, Tawfik Gharbaoui, Ashwin Krishnan, Biman Pal, Sagar R Shakya, Antonio Garrido Montalban, John W Adams, Juan Ramirez, Dominic P Behan, Anna Shifrina, Anthony Blackburn, Tina Leakakos, Yunqing Shi, Michael Morgan, Abu Sadeque, Weichao Chen, David J Unett, Ibragim Gaidarov, Xiaohua Chen, Steve Chang, Hsin-Hui Shu, Shiu-Feng Tung, Graeme Semple
The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays...
January 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28059509/pyrimidinyl-biphenylureas-identification-of-new-lead-compounds-as-allosteric-modulators-of-the-cannabinoid-receptor-cb1
#10
Leepakshi Khurana, Bo-Qiao Fu, Anantha L Duddupudi, Yu-Hsien Liao, Sri Sujana Immadi, Debra A Kendall, Dai Lu
The allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB1) and antagonized G protein coupling. This compound demonstrated potent anorectic effects similar to the CB1 antagonist rimonabant that once was marketed for the treatment of obesity, suggesting a new chemical entity for the discovery of antiobesity drugs. To increase structural diversity of this class of CB1 ligands, we designed and synthesized two classes of novel analogues, in which the pyridine ring of 2 was replaced by a pyrimidine ring...
January 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28099811/nanomolar-potency-aminophenyl-1-3-5-triazine-activators-of-the-cystic-fibrosis-transmembrane-conductance-regulator-cftr-chloride-channel-for-pro-secretory-therapy-of-dry-eye-diseases
#11
Sujin Lee, Puay-Wah Phuan, Christian M Felix, Joseph-Anthony Tan, Marc H Levin, Alan S Verkman
Dry eye disorders are a significant health problem for which limited therapeutic options are available. CFTR is a major pro-secretory chloride channel at the ocular surface. We previously identified, by high-throughput screening, aminophenyl-1,3,5-triazine CFTRact-K089 (1) that activated CFTR with EC50 ~250 nM, which when delivered topically increased tear fluid secretion in mice and showed efficacy in an experimental dry eye model. Here, functional analysis of aminophenyl-1,3,5-triazine analogs elucidated structure-activity relationships for CFTR activation and identified substantially more potent analogs than 1...
January 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28098449/targeting-type-2-diabetes-with-c-glucosyl-dihydrochalcones-as-selective-sodium-glucose-co-transporter-2-sglt2-inhibitors-synthesis-and-biological-evaluation
#12
Ana R Jesus, Diogo Vila-Viçosa, Miguel Machuqueiro, Ana P Marques, Timothy M Dore, Amélia P Rauter
Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC50 = 9-23 nM) were considerably weaker inhibitors of SGLT1 (IC50 = 10-19 μM)...
January 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28068095/potent-inhibition-of-nitric-oxide-releasing-bifendate-derivatives-against-drug-resistant-k562-a02-cells-in-vitro-and-in-vivo
#13
Xiaoke Gu, Zhangjian Huang, Zhiguang Ren, Xiaobo Tang, Rongfang Xue, Xiaojun Luo, Sixun Peng, Hui Peng, Bin Lu, Jide Tian, Yihua Zhang
Multidrug resistance is a major obstacle to successful chemotherapy for leukemia. In this study, a series of nitric oxide (NO)-releasing bifendate derivatives (7a-n) were synthesized. Biological evaluation indicated that the most active compound (7a) produced relatively high levels of NO and significantly inhibited the proliferation of drug-resistant K562/A02 cells in vitro and in vivo. In addition, 7a induced the mitochondrial tyrosine nitration and the intracellular accumulation of rhodamine 123 by inhibiting P-gp activity in K562/A02 cells...
January 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28052200/structure-activity-relationship-of-the-antimalarial-ozonide-artefenomel-oz439
#14
Yuxiang Dong, Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Francis C K Chiu, Jacques Chollet, Manickam Dhanasekaran, Christopher D Hein, Petros Papastogiannidis, Julia Morizzi, David M Shackleford, Helena Barker, Eileen Ryan, Christian Scheurer, Yuanqing Tang, Qingjie Zhao, Lin Zhou, Karen L White, Heinrich Urwyler, William N Charman, Hugues Matile, Sergio Wittlin, Susan A Charman, Jonathan L Vennerstrom
Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7...
January 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28051300/design-and-synthesis-of-potent-and-highly-selective-orexin-1-receptor-antagonists-with-a-morphinan-skeleton-and-their-pharmacologies
#15
Hiroshi Nagase, Naoshi Yamamoto, Masahiro Yata, Sayaka Ohrui, Takahiro Okada, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Yasuhiro Ogawa, Shigeto Hirayama, Daisuke Kuroda, Yurie Watanabe, Hiroaki Gouda, Masashi Yanagisawa
Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine...
January 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28045523/design-of-potent-and-selective-cathepsin-g-inhibitors-based-on-the-sunflower-trypsin-inhibitor-1-scaffold
#16
Joakim E Swedberg, Choi Yi Li, Simon J de Veer, Conan K Wang, David J Craik
Neutrophils are directly responsible for destroying invading pathogens via reactive oxygen species, antimicrobial peptides, and neutrophil serine proteases (NSPs). Imbalance between NSP activity and endogenous protease inhibitors is associated with chronic inflammatory disorders, and engineered inhibitors of NSPs are a potential therapeutic pathway. In this study we characterized the extended substrate specificity (P4-P1) of the NSP cathepsin G using a peptide substrate library. Substituting preferred cathepsin G substrate sequences into sunflower trypsin inhibitor-1 (SFTI-1) produced a potent cathepsin G inhibitor (Ki = 0...
January 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28094938/in-vitro-and-in-vivo-evaluation-of-fully-substituted-5-3-ethoxy-3-oxopropynyl-4-ethoxycarbonyl-1-2-3-triazolyl-glycosides-as-original-nucleoside-analogs-to-circumvent-resistance-in-myeloid-malignancies
#17
Hella Amdouni, Guillaume Robert, Mohsine Driowya, Nathan Furstoss, Camille Métier, Alix Dubois, Maeva Dufies, Marwa Zerhouni, François Orange, Sandra Lacas-Gervais, Khalid Bougrin, Anthony R Martin, Patrick Auberger, Rachid Benhida
A series of nucleoside analogs bearing a 1,4,5-trisubstituted-1,2,3-triazole aglycone was synthesized using a straightforward click/electrophilic addition or click/oxidative coupling tandem procedures. SAR analysis, using cell culture assays, led to the discovery of a series of compounds belonging to the 5-alkynyl-1,2,3-triazole family that exhibits potent antileukemic effects on several hematologic malignancies including chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS) either sensitive or resistant to their respective therapy...
January 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28094524/antimalarial-pyrido-1-2-a-benzimidazoles-lead-optimization-parasite-life-cycle-stage-profile-mechanistic-evaluation-killing-kinetics-and-in-vivo-oral-efficacy-in-a-mouse-model
#18
Kawaljit Singh, John Okombo, Christel Brunschwig, Ferdinand Ndubi, Linley Barnard, Chad Wilkinson, Peter M Njogu, Mathew Njoroge, Lizahn Laing, Marta Machado, Miguel Prudêncio, Janette Reader, Mariette E Botha, Sindisiwe H Nondaba, Lyn-Marie Birkholtz, Sonja Lauterbach, Alisje Churchyard, Theresa L Coetzer, Jeremy N Burrows, Clive Leonard Yeates, Paolo Denti, Lubbe Wiesner, Timothy J Egan, Sergio Wittlin, Kelly Chibale
Further structure activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials, have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of haemozoin formation possibly contributes to the mechanism of action.
January 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28055204/design-synthesis-of-novel-potent-selective-orally-bioavailable-adenosine-a2a-receptor-antagonists-and-their-biological-evaluation
#19
Sujay Basu, Dinesh A Barawkar, Sachin Thorat, Yogesh D Shejul, Meena Patel, Minakshi Naykodi, Vaibhav Jain, Yogesh Salve, Vandna Prasad, Sumit Chaudhary, Indraneel Ghosh, Ganesh Bhat, Azfar Quraishi, Harish Patil, Shariq Ansari, Suraj Menon, Vishal Unadkat, Rhishikesh Thakare, Madhav S Seervi, Ashwinkumar V Meru, Siddhartha De, Ravi K Bhamidipati, Sreekanth R Rouduri, Venkata P Palle, Anita Chug, Kasim A Mookhtiar
Our initial structure-activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A2A adenosine receptor (A2AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A2A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability...
January 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28045525/a-macrocyclic-agouti-related-protein-nle-4-dphe-7-%C3%AE-melanocyte-stimulating-hormone-chimeric-scaffold-produces-subnanomolar-melanocortin-receptor-ligands
#20
Mark D Ericson, Katie T Freeman, Sathya M Schnell, Carrie Haskell-Luevano
The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R...
January 17, 2017: Journal of Medicinal Chemistry
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