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Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/28938069/molecular-recognition-of-agonists-and-antagonists-by-the-nucleotide-activated-g-protein-coupled-p2y2-receptor
#1
Muhammad Rafehi, Alexander Neumann, Younis Baqi, Enas M Malik, Michael Wiese, Vigneshwaran Namasivayam, Christa E Müller
A homology model of the nucleotide-activated P2Y2R was created based on the X-ray structures of the P2Y1 and P2Y12 receptors. Docking studies were performed, and receptor mutants were created to probe the identified binding interactions. Mutation of residues predicted to interact with the ribose (Arg110) and the phosphates of the nucleotide agonists (Arg265, Arg292) or that contribute indirectly to binding (Tyr288) abolished activity. The Y114F, R194A, and F261A mutations led to inactivity of diadenosine tetraphosphate and to a reduced response of UTP...
September 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28937774/selective-non-steroidal-glucocorticoid-receptor-modulators-for-the-inhaled-treatment-of-pulmonary-diseases
#2
Martin Hemmerling, Stinabritt Nilsson, Karl Edman, Stefan Eirefelt, Wayne Russell, Ramon Hendrickx, Eskil Johnsson, Carina Kärrman-Mårdh, Markus Berger, Hartmut Rehwinkel, Anna Abrahamsson, Jan Dahm Eacute N, Anders R Eriksson, Balint Gabos, Krister Henriksson, Nafizal Hossain, Svetlana Ivanova, Anne-Helene Jansson, Tina J Jensen, Anders Jerre, Henrik Johansson, Tomas Klingstedt, Matti Lepistö, Martin Lindsjö, Irene Mile, Grigorios Nikitidis, John Steele, Ulrika Tehler, Lisa Wissler, Thomas Hansson
A class of potent, non-steroidal, selective indazole ether based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft drug strategy was implemented to ensure rapid elimination of drug candidates and minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution...
September 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28895732/a-new-series-of-succinimido-ferrociphenols-and-related-heterocyclic-species-induce-strong-antiproliferative-effects-especially-against-ovarian-cancer-cells-resistant-to-cisplatin
#3
Pascal Pigeon, Yong Wang, Siden Top, Feten Najlaoui, Maria Concepcion Garcia Alvarez, Jérôme Bignon, Michael J McGlinchey, Gérard Jaouen
Ferrociphenols are known to display anticancer properties by original mechanisms dependent on redox properties and generation of active metabolites such as quinone methides. Recent studies have highlighted the positive impact of oxidative stress on chemosensitivity and prognosis of ovarian cancer patients. Ovarian adenocarcinomas are shown to be an excellent model for defining the impact of selected ferrociphenols as new therapeutic drugs for such cancers. This work describes the syntheses and preliminary mechanistic research of unprecedented multitargeting heterocyclic ferrociphenols bearing either a succinimidyl or phthalimidyl group that show exceptional antiproliferative behavior against epithelial ovarian cancer cells resistant to cisplatin...
September 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28934547/multifunctional-hybrid-compounds-derived-from-2-2-5-dioxopyrrolidin-1-yl-3-methoxypropanamides-with-anticonvulsant-and-antinociceptive-properties
#4
Michał Abram, Mirosław Zagaja, Szczepan Mogilski, Marta Andres-Mach, Gniewomir Latacz, Sebastian Baś, Jarogniew J Łuszczki, Katarzyna Kieć-Kononowicz, Krzysztof Kamiński
The focused set of new pyrrolidine-2,5-diones as potential broad-spectrum hybrid anticonvulsants was described. These derivatives integrate on the common structural scaffold the chemical fragments of well-known antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. Such hybrids demonstrated effectiveness in two of the most widely used animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model. Compound 33 showed the highest anticonvulsant activity in these models (ED50 MES = 79...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28933851/design-and-structure-guided-development-of-novel-inhibitors-of-the-xeroderma-pigmentosum-group-a-xpa-protein-dna-interaction
#5
Navnath S Gavande, Pamela VanderVere-Carozza, Akaash K Mishra, Tyler L Vernon, Katherine S Pawelczak, John J Turchi
XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA-DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 μM and 1.3 ± 0.22 μM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28933846/inhibition-of-calcium-dependent-protein-kinase-1-cdpk1-by-pyrazolopyrimidine-analogs-decreases-establishment-and-reoccurrence-of-central-nervous-system-disease-by-toxoplasma-gondii
#6
Florentine U Rutaganira, Jennifer Barks, Mary Savari Dhason, Qiuling Wang, Michael Steven Lopez, Shaojun Long, Joshua B Radke, Nathaniel G Jones, Amarendar R Maddirala, James W Janetka, Majida El Bakkouri, Raymond Hui, Kevan M Shokat, L David Sibley
Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are essential to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goals of increasing selectivity over host enzymes, improving anti-parasite potency, and improving metabolic stability...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28933844/mind-the-metal-a-fragment-library-derived-zinc-impurity-binds-the-e2-ubiquitin-conjugating-enzyme-ube2t-and-induces-structural-rearrangements
#7
Francesca E Morreale, Andrea Testa, Viduth K Chaugule, Alessio Bortoluzzi, Alessio Ciulli, Helen Walden
Efforts to develop inhibitors, activators and effectors of biological reactions using small molecule libraries are often hampered by interference compounds, artifacts and false positives that permeate the pool of initial hits. Here we report the discovery of a promising initial hit compound targeting the Fanconi anemia ubiquitin-conjugating enzyme Ube2T and describe its biophysical and biochemical characterization. Analysis of the co-crystal structure led to the identification of a contaminating zinc ion as solely responsible for the observed effects...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28933546/rational-design-of-selective-adenine-based-scaffolds-for-inactivation-of-bacterial-histidine-kinases
#8
Manibarsha Goswami, Kaelyn E Wilke, Erin E Carlson
Bacterial histidine kinases (HKs) are quintessential regulatory enzymes found ubiquitously in bacteria. Apart from regulatory roles, they are also involved in the production of virulence factors and conferring resistance to various antibiotics in pathogenic microbes. We have previously reported compounds that inhibit multiple HKs by targeting the conserved catalytic and ATP-binding (CA) domain. Herein, we conduct a detailed structure-activity relationship assessment of adenine-based inhibitors using biochemical and docking methods...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28892629/development-of-4-cyanophenyl-glycine-derivatives-as-reversible-inhibitors-of-lysine-specific-demethylase-1
#9
Daniel P Mould, Cristina Alli, Ulf Bremberg, Sharon Cartic, Allan M Jordan, Matthis Geitmann, Alba Maiques-Diaz, Alison E McGonagle, Tim C P Somervaille, Gary J Spencer, Fabrice Turlais, Donald Ogilvie
Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1)...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28892388/novel-radiolabeled-vanilloid-with-enhanced-specificity-for-human-transient-receptor-potential-vanilloid-1-trpv1
#10
Larry V Pearce, Jihyae Ann, Aeran Jung, Shivaji A Thorat, Brienna K A Herold, Amelework D Habtemichael, Peter M Blumberg, Jeewoo Lee
Transient receptor potential vanilloid 1 (TRPV1) has emerged as a promising therapeutic target. While radiolabeled resiniferatoxin (RTX) has provided a powerful tool for characterization of vanilloid binding to TRPV1, TRPV1 shows 20-fold weaker binding to the human TRPV1 than to the rodent TRPV1. We now describe a tritium radiolabeled synthetic vanilloid antagonist, 1-((2-(4-(methyl-[(3)H])piperidin-1-yl-4-[(3)H])-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)urea ([(3)H]MPOU), that embodies improved absolute affinity for human TRPV1 and improved synthetic accessibility...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28892380/gne-781-a-highly-advanced-potent-and-selective-bromodomain-inhibitor-of-cyclic-adenosine-monophosphate-response-element-binding-protein-binding-protein-cbp
#11
F Anthony Romero, Jeremy Murray, Kwong Wah Lai, Vickie Tsui, Brian K Albrecht, Le An, Maureen H Beresini, Gladys de Leon Boenig, Sarah M Bronner, Emily W Chan, Kevin X Chen, Zhongguo Chen, Edna F Choo, Kyle Clagg, Kevin Clark, Terry D Crawford, Patrick Cyr, Denise de Almeida Nagata, Karen E Gascoigne, Jane L Grogan, Georgia Hatzivassiliou, Wei Huang, Thomas L Hunsaker, Susan Kaufman, Stefan G Koenig, Ruina Li, Yingjie Li, Xiaorong Liang, Jiangpeng Liao, Wenfeng Liu, Justin Ly, Jonathan Maher, Colin Masui, Mark Merchant, Yingqing Ran, Alexander M Taylor, John Wai, Fei Wang, Xiaocang Wei, Dong Yu, Bing-Yan Zhu, Xiaoyu Zhu, Steven Magnuson
Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28885834/small-molecule-inhibitors-simultaneously-targeting-cancer-metabolism-and-epigenetics-discovery-of-novel-nicotinamide-phosphoribosyltransferase-nampt-and-histone-deacetylase-hdac-dual-inhibitors
#12
Guoqiang Dong, Wei Chen, Xia Wang, Xinglin Yang, Tianying Xu, Pei Wang, Wannian Zhang, Yu Rao, Chaoyu Miao, Chunquan Sheng
Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis, and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM)...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28929759/selective-inhibitors-of-dual-leucine-zipper-kinase-dlk-map3k12-with-activity-in-a-model-of-alzheimer-s-disease
#13
Snahel Patel, William J Meilandt, Rebecca I Erickson, Jinhua Chen, Gauri Deshmukh, Anthony A Estrada, Reina N Fuji, Paul Gibbons, Amy Gustafson, Seth F Harris, Jose Imperio, Wendy Liu, Xingrong Liu, Yichin Liu, Joseph P Lyssikatos, Changyou Ma, Jianping Yin, Joseph W Lewcock, Michael Siu
Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors...
September 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28929756/fragment-based-discovery-and-optimization-of-enzyme-inhibitors-by-docking-of-commercial-chemical-space
#14
Axel Rudling, Robert Gustafsson, Ingrid Almlöf, Evert J Homan, Martin Scobie, Ulrika Warpman Berglund, Thomas Helleday, Pål Stenmark, Jens Carlsson
Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Despite that fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated...
September 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28929751/structural-biology-inspired-discovery-of-novel-kras-pde%C3%AE-inhibitors
#15
Yan Jiang, Chunlin Zhuang, Long Chen, Junjie Lu, Guoqiang Dong, Zhenyuan Miao, Wannian Zhang, Jian Li, Chunquan Sheng
Structural biology is a powerful tool for investigating the stereospecific interactions between a protein and its ligand. Herein, an unprecedented chiral binding pattern was observed for inhibitors of KRAS-PDEδ interactions. Virtual screening and X-ray crystallography studies revealed that two enantiomers of a racemic inhibitor could bind at different sites. Fragment-based drug design was used to identify highly potent PDEδ inhibitors that can be used as promising lead compounds for target validation and antitumor drug development...
September 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28858511/anchimerically-activated-protides-as-inhibitors-of-cap-dependent-translation-and-inducers-of-chemosensitization-in-mantle-cell-lymphoma
#16
Aniekan Okon, JingJing Han, Surendra Dawadi, Christos Demosthenous, Courtney C Aldrich, Mamta Gupta, Carston R Wagner
The cellular delivery of nucleotides through various pronucleotide strategies has expanded the utility of nucleosides as a therapeutic class. Although highly successful, the highly popular ProTide system relies on a four-step enzymatic and chemical process to liberate the corresponding monophosphate. To broaden the scope and reduce the number of steps required for monophosphate release, we have developed a strategy that depends on initial chemical activation by a sulfur atom of a methylthioalkyl protecting group, followed by enzymatic hydrolysis of the resulting phosphoramidate monoester...
September 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28926247/beyond-the-rule-of-5-lessons-learned-from-abbvie-s-drugs-and-compound-collection
#17
David A DeGoey, Hui-Ju Chen, Philip B Cox, Michael D Wendt
Recently, there has been an increasing focus on the pursuit of targets considered to be less-druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond Rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects...
September 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28926243/are-we-there-yet-applying-thermodynamic-and-kinetic-profiling-on-embryonic-ectoderm-development-eed-hit-to-lead-program
#18
Ying Wang, Rohinton P Edalji, Sanjay C Panchal, Chaohong C Sun, Stevan W Djuric, Anil Vasudevan
It is advocated that kinetic and thermodynamic profiling of bioactive compounds should be incorporated and utilized as complementary tools for hit and lead optimizations in drug discovery. To assess their applications in the EED hit-to-lead optimization process, large amount of thermodynamic and kinetic data were collected and analyzed via isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR), respectively. Slower dissociation rates (koff) of the lead compounds were observed as the program progressed...
September 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28925695/nanomolar-inhibitors-of-glycogen-phosphorylase-based-on-%C3%AE-d-glucosaminyl-heterocycles-a-combined-synthetic-enzyme-kinetic-and-protein-crystallography-study
#19
Eva Bokor, Efthimios Kyriakis, Theodora Ga Solovou, Csenge Koppány, Anastassia L Kantsadi, Katalin E Szabó, Andrea Szakács, Georgios A Stravodimos, Tibor Docsa, Vassiliki T Skamnaki, Spyros E Zographos, Pál Gergely, Demetres D Leonidas, László Somsák
Aryl substituted 1-(β-D-glucosaminyl)-1,2,3-triazoles as well as C-β-D-glucosaminyl 1,2,4-triazoles and imidazoles were synthesized and tested as inhibitors against muscle and liver isoforms of glycogen phosphorylase (GP). While the N-β-D-glucosaminyl 1,2,3-triazoles showed weak or no inhibition, the C-β-D-glucosaminyl derivatives had potent activity and the best inhibitor was the 2-(β-D-glucosaminyl)-4(5)-(2-naphthyl)-imidazole with a Ki value of 143 nM against human liver GPa. An X-ray crystallography study of the rabbit muscle GPb inhibitor complexes revealed structural features of the strong binding, and offered an explanation for the differences in inhibitory potency between glucosyl and glucosaminyl derivatives and also for the differences between imidazole and 1,2,4-triazole analogues...
September 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28829913/virtual-screening-of-acyclovir-derivatives-as-potential-antiviral-agents-design-synthesis-and-biological-evaluation-of-new-acyclic-nucleoside-protides
#20
Marco Derudas, Christophe Vanpouille, Davide Carta, Sonia Zicari, Graciela Andrei, Robert Snoeck, Andrea Brancale, Leonid Margolis, Jan Balzarini, Christopher McGuigan
Following our findings on the anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate kinase, and human DNA polymerase γ. A total of 39 new phosphate prodrugs were synthesized and evaluated against HIV-1 (in vitro and ex vivo human tonsillar tissue system) and human herpes viruses...
September 19, 2017: Journal of Medicinal Chemistry
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