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Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/28448141/correction-to-design-of-potent-and-druglike-nonphenolic-inhibitors-for-catechol-o-methyltransferase-derived-from-a-fragment-screening-approach-targeting-the-s-adenosyl-l-methionine-pocket
#1
Christian Lerner, Roland Jakob-Roetne, Bernd Buettelmann, Andreas Ehler, Markus G Rudolph, Rosa María Rodríguez Sarmiento
No abstract text is available yet for this article.
April 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28448133/design-of-novel-exendin-based-dual-glucagon-like-peptide-1-glp-1-glucagon-receptor-agonists
#2
Andreas Evers, Torsten Haack, Martin Lorenz, Martin Bossart, Ralf Elvert, Bernd Henkel, Siegfried Stengelin, Michael Kurz, Maike Glien, Angela Dudda, Katrin Lorenz, Dieter Kadereit, Michael Wagner
Dual activation of the glucagon-like peptide 1 (GLP-1) and glucagon receptor has the potential to lead to a novel therapy principle for the treatment of diabesity. Here, we report a series of novel peptides with dual activity on these receptors that were discovered by rational design. Based on sequence analysis and structure-based design, structural elements of glucagon were engineered into the selective GLP-1 receptor agonist exendin-4, resulting in hybrid peptides with potent dual GLP-1/glucagon receptor activity...
April 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28447791/discovery-of-a-potent-selective-renal-sodium-dependent-glucose-cotransporter-2-sglt2-inhibitor-hsk0935-for-the-treatment-of-type-2-diabetes
#3
Yao Li, Zongjun Shi, Lei Chen, Suxin Zheng, Sheng Li, Bo Xu, Zhenhong Liu, Jianyu Liu, Chongyang Deng, Fei Ye
A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843 fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring closing cascade reaction to incorporate a double ketal 1-methoxy-6, 8- dioxabicyclo[3.2.1]octane ring system...
April 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28447789/exploring-the-role-of-n-6-substituents-in-potent-dual-acting-5-c-ethyl-tetrazolyl-adenosine-derivatives-synthesis-binding-functional-assays-and-antinociceptive-effects-in-mice
#4
Riccardo Petrelli, Mirko Scortichini, Sonja Kachler, Serena Boccella, Carmen Cerchia, Ilaria Torquati, Fabio Del Bello, Daniela Salvemini, Ettore Novellino, Livio Luongo, Sabatino Maione, Kenneth A Jacobson, Antonio Lavecchia, Karl-Norbert Klotz, Loredana Cappellacci
Structural determinants of affinity of N(6)-substituted-5'-C-(ethyl-tetrazol-2-yl)-adenosine and 2-chloro-adenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N(6)-cycloalkyl and 3-halo-benzyl groups furnished potent dual acting A1AR agonists and A3AR antagonists. 4 was the most potent dual acting human (h) A1AR agonist (Ki = 0.45 nM) and A3AR antagonist (Ki = 0.31 nM) and highly selective versus A2A; 11 and 26 were most potent at both h and rat (r) A3AR...
April 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28399367/determination-of-in-vitro-and-in-silico-indexes-for-the-modeling-of-blood-brain-barrier-partitioning-of-drugs-via-micellar-and-immobilized-artificial-membrane-liquid-chromatography
#5
Giacomo Russo, Lucia Grumetto, Roman Szucs, Francesco Barbato, Frederic Lynen
In the present work, 79 structurally unrelated analytes were taken into account and their chromatographic retention coefficients, measured by immobilized artificial membrane liquid chromatography (IAM-LC) and by micellar liquid chromatography (MLC) employing sodium dodecyl sulfate (SDS) as surfactant, were determined. Such indexes, along with topological and physicochemical parameters calculated in silico, were subsequently used for the development of blood-brain barrier passage-predictive statistical models using partial least-squares (PLS) regression...
April 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28383902/prediction-of-antibiotic-interactions-using-descriptors-derived-from-molecular-structure
#6
Daniel J Mason, Ian Stott, Stephanie Ashenden, Zohar B Weinstein, Idil Karakoc, Selin Meral, Nurdan Kuru, Andreas Bender, Murat Cokol
Combination antibiotic therapies are clinically important in the fight against bacterial infections. However, the search space of drug combinations is large, making the identification of effective combinations a challenging task. Here, we present a computational framework that uses substructure profiles derived from the molecular structures of drugs and predicts antibiotic interactions. Using a previously published data set of 153 drug pairs, we showed that substructure profiles are useful in predicting synergy...
April 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28445047/development-of-selective-orally-active-gpr4-antagonists-with-modulatory-effects-on-nociception-inflammation-and-angiogenesis
#7
Juraj Velcicky, Wolfgang Miltz, Berndt Oberhauser, David Orain, Andrea Vaupel, Klaus Weigand, Janet Dawson King, Amanda Littlewood-Evans, Mark Nash, Roland Feifel, Pius Loetscher
A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg...
April 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28445046/lead-discovery-of-dual-g-quadruplex-stabilizers-and-poly-adp-ribose-polymerases-parps-inhibitors-a-new-avenue-in-anticancer-treatment
#8
Erica Salvati, Lorenzo Botta, Jussara Amato, Francesco Saverio Di Leva, Pasquale Zizza, Antimo Gioiello, Bruno Pagano, Grazia Graziani, Madalena Tarsounas, Antonio Randazzo, Ettore Novellino, Annamaria Biroccio, Sandro Cosconati
G-quadruplex stabilizers are an established opportunity in anticancer chemotherapy. To circumvent the antiproliferative effects of G4 ligands, cancer cells recruit PARP enzymes at telomeres. Herein, starting from the structural similarity of a potent G4 ligand previously discovered by our group and a congeneric PARP inhibitor, a library of derivatives was synthesized to discover the first dual G4/PARP ligand. We demonstrate that a properly decorated thieno[3,2-c]quinolin-4(5H)-one stabilizes the G4 fold in vitro and in cells, induces a DNA damage response localized to telomeres, inhibits PARylation in cells and has an antiproliferative effect in BRCA2 deficient tumor cells...
April 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28445037/discovery-of-5-azaindazole-gne-955-as-a-potent-pan-pim-inhibitor-with-optimized-bioavailability
#9
Xiaojing Wang, Aleksandr Kolesnikov, Suzanne Tay, Grace Chan, Qi Chao, Steven Do, Jason Drummond, Allen J Ebens, Ning Liu, Justin Q Ly, Eric Harstad, Huiyong Hu, John G Moffat, Veerendra Munugalavadla, Jeremy M Murray, Dionysos Slaga, Vickie Tsui, Matthew Volgraf, Heidi J A Wallweber, Jae H Chang
Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse...
April 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28441491/a-naturally-occurring-isoform-specific-probe-for-highly-selective-and-sensitive-detection-of-human-cytochrome-p450-3a5
#10
Jing-Jing Wu, Yun-Feng Cao, Liang Feng, Yu-Qi He, James Y Hong, Tong-Yi Dou, Ping Wang, Da-Cheng Hao, Guang-Bo Ge, Ling Yang
Cytochrome P450 (CYP) 3A5 characterized with polymorphic and extensive expression in multiple tissues is the most important P450 enzyme among the minor CYP3A isoforms. However, a selective and sensitive probe for CYP3A5 remains unavailable. In this study, we identified and characterized a naturally-occurring lignan 12 (Schisantherin E) as an isoform-specific probe for selective detection of CYP3A5 activity in complex biological samples. With thorough characterization including LC-MS and NMR, we found that 12 can be metabolized by CYP3A5 to generate a major metabolite 2-O-demethylated 12...
April 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28441483/discovery-of-a-novel-class-of-survival-motor-neuron-2-splicing-modifiers-for-the-treatment-of-spinal-muscular-atrophy
#11
Emmanuel Pinard, Luke Green, Michael Reutlinger, Marla Weetall, Nikolai N Naryshkin, John Baird, Karen S Chen, Sergey V Paushkin, Friedrich Metzger, Hasane Ratni
Spinal muscular atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene, resulting in low levels of functional SMN protein. We have reported recently the identification of small molecules (coumarins, iso-coumarins and pyrido-pyrimidinones) that modify the alternative splicing of SMN2, a paralogous gene to SMN1, restoring the survival motor neuron (SMN) protein level in mouse models of SMA. Herein, we report our efforts to identify a novel chemotype as one strategy to potentially circumvent safety concerns from earlier derivatives, such as in-vitro phototoxicity and in-vitro mutagenicity associated with compounds 1 and 2 or the in-vivo retinal findings observed in a long term chronic tox study with 3 at high exposures only...
April 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28406646/transforming-sphingosine-kinase-1-inhibitors-into-dual-and-sphingosine-kinase-2-selective-inhibitors-design-synthesis-and-in-vivo-activity
#12
Elizabeth S Childress, Yugesh Kharel, Anne M Brown, David R Bevan, Kevin R Lynch, Webster L Santos
Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with its five G-protein coupled receptors (S1P1-5) to regulate cell growth and survival and has been implicated in a variety of diseases including cancer and sickle cell disease. As the key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmaceutical inhibition. In this article, we describe the design, synthesis, and biological evaluation of aminothiazole-based guanidine inhibitors of SphK...
April 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28437106/allosteric-targeting-of-the-fanconi-anemia-ubiquitin-conjugating-enzyme-ube2t-by-fragment-screening
#13
Francesca E Morreale, Alessio Bortoluzzi, Viduth K Chaugule, Connor Arkinson, Helen Walden, Alessio Ciulli
Ube2T is the E2 ubiquitin-conjugating enzyme of the Fanconi anemia DNA repair pathway and it's overexpressed in several cancers, representing an attractive target for the development of inhibitors. Despite the extensive efforts in targeting the ubiquitin system, very few E2 binders have currently been discovered. Herein we report the identification of a new allosteric pocket on Ube2T through a fragment screening using biophysical methods. Several fragments binding to this site inhibit ubiquitin conjugation in vitro...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28436655/investigating-the-antibacterial-activity-of-biphenylthiazoles-against-methicillin-and-vancomycin-resistant-staphylococcus-aureus-mrsa-and-vrsa
#14
Mohamed Hagras, Haroon Mohammad, Mohamed S Mandour, Youssef A Hegazy, Adel Ghiaty, Mohamed N Seleem, Abdelrahman S Mayhoub
Phenylthiazoles were reported previously as a new scaffold with antibacterial activity against an array of multidrug-resistant staphylococci. However, their promising antibacterial activity was hampered in large part by their short half-life due to excessive hepatic clearance. Close inspection of the structure-activity-relationships (SAR) of the phenylthiazoles revealed two important structural features necessary for antibacterial activity (a nitrogenous and a lipophilic component). Incorporating the nitrogenous part within a pyrimidine ring resulted in analogues with a prolonged half-life, while the biphenyl moiety revealed the most potent analogue 1b...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28418242/slow-but-steady-wins-the-race-dissimilarities-among-new-dual-inhibitors-of-the-wild-type-and-the-v27a-mutant-m2-channels-of-influenza-a-virus
#15
Marta Barniol-Xicota, Sabrina Gazzarrini, Eva Torres, Yanmei Hu, Jun Wang, Lieve Naesens, Anna Moroni, Santiago Vázquez
New insights on the amantadine resistance mechanism of the V27A mutant were obtained through the study of novel, easily accessible 4-(1- and 2-adamantyl)piperidines, identified as dual binders of the wild-type and V27A mutant M2 channels of influenza A virus. Their antiviral activity and channel blocking ability were determined using cell-based assays and two-electrode voltage clamp (TEVC) technique on M2 channels, respectively. In addition, electrophysiology experiments revealed two interesting findings: (i) these inhibitors display a different behavior against the wild-type versus V27A mutant A/M2 channels, and (ii) the compounds display antiviral activity when they have kd equal or smaller than 10(-6) while they do not exhibit antiviral activity when kd is 10(-5) or higher although they may show blocking activity in the TEV assay...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28410442/development-of-an-acrylate-derivative-targeting-the-nlrp3-inflammasome-for-the-treatment-of-inflammatory-bowel-disease
#16
Mattia Cocco, Carolina Pellegrini, Helios Martínez-Banaclocha, Marta Giorgis, Elisabetta Marini, Annalisa Costale, Gianluca Miglio, Matteo Fornai, Luca Antonioli, Gloria López-Castejón, Ana Tapia-Abellán, Diego Angosto, Iva Hafner-Bratkovič, Luca Regazzoni, Corrado Blandizzi, Pablo Pelegrín, Massimo Bertinaria
Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of inflammatory bowel disease. In this work, we report the design, synthesis, and biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a nontoxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β release from macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interfere with NLRP3 activation in cells...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28409644/amphiphilic-tobramycin-lysine-conjugates-sensitize-multidrug-resistant-gram-negative-bacteria-to-rifampicin-and-minocycline
#17
Yinfeng Lyu, Xuan Yang, Sudeep Goswami, Bala Kishan Gorityala, Temilolu Idowu, Ronald Domalaon, George G Zhanel, Anshan Shan, Frank Schweizer
Chromosomally encoded low membrane permeability and highly efficient efflux systems are major mechanisms by which Pseudomonas aeruginosa evades antibiotic actions. Our previous reports have shown that amphiphilic tobramycin-fluoroquinolone hybrids can enhance efficacy of fluoroquinolone antibiotics against multidrug-resistant (MDR) P. aeruginosa isolates. Herein, we report on a novel class of tobramycin-lysine conjugates containing an optimized amphiphilic tobramycin-C12 tether that sensitize Gram-negative bacteria to legacy antibiotics...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28409639/design-synthesis-and-biological-evaluation-of-dimorpholine-substituted-thienopyrimidines-as-potential-class-i-pi3k-mtor-dual-inhibitors
#18
Miao Zhan, Yufang Deng, Lifeng Zhao, Guoyi Yan, Fangying Wang, Ye Tian, Lanxi Zhang, Hongxia Jiang, Yuanwei Chen
Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. A series of dimorpholine substituted thienopyrimidine derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor, which had an approximately 8-fold improvement in mTOR inhibition relative to the class I PI3K inhibitor 1 (pictilisib, GDC-0941). Western blot analysis confirmed the 14o mechanistic modulation of the cellular PI3K/AKT/mTOR pathway through inhibiting phosphorylation of both AKT and S6 in human cancer cell lines...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28406300/synthesis-and-characterization-of-tetrahydropyran-based-bacterial-topoisomerase-inhibitors-with-antibacterial-activity-against-gram-negative-bacteria
#19
Jean-Philippe Surivet, Cornelia Zumbrunn, Thierry Bruyère, Daniel Bur, Christopher Kohl, Hans H Locher, Peter Seiler, Eric A Ertel, Patrick Hess, Michel Enderlin-Paput, Stéphanie Enderlin-Paput, Jean-Christophe Gauvin, Azely Mirre, Christian Hubschwerlen, Daniel Ritz, Georg Rueedi
There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens and no target-mediated cross-resistance with fluoroquinolones. We report our research efforts aimed at expanding the antibacterial spectrum of this class of molecules toward difficult-to-treat Gram-negative pathogens...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28406299/discovery-and-optimization-of-isoquinoline-ethyl-ureas-as-antibacterial-agents
#20
Philippe Panchaud, Thierry Bruyère, Anne-Catherine Blumstein, Daniel Bur, Alain Chambovey, Eric A Ertel, Markus Gude, Christian Hubschwerlen, Loïc Jacob, Thierry Kimmerlin, Thomas Pfeifer, Lars Prade, Peter Seiler, Daniel Ritz, Georg Rueedi
Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site...
April 24, 2017: Journal of Medicinal Chemistry
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