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Journal of Medicinal Chemistry

Domenico Schillaci, Virginia Spanò, Barbara Parrino, Anna Carbone, Alessandra Montalbano, Paola Barraja, Patrizia Diana, Girolamo Cirrincione, Stella Cascioferro
There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections...
June 20, 2017: Journal of Medicinal Chemistry
Valeria Famiglini, Giuseppe La Regina, Antonio Coluccia, Domiziana Masci, Andrea Brancale, Roger Badia, Eva Riveira Muñoz, Jose A Este, Emmanuele Crespan, Alessandro Brambilla, Giovanni Maga, Myriam Catalano, Cristina Limatola, Francesca Romana Romana Formica, Roberto Cirilli, Ettore Novellino, Romano Silvestri
We designed and synthesized a series of chiral indolyarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs 8-37 showed potent inhibition of the HIV-1 WT NL4-3 strain and of the mutant K103N, Y181C, Y188L and K103N-Y181C HIV-1 strains. Six racemic mixtures, 8, 23-25, 31 and 33, were separated at semipreparative level into their pure enantiomers. The (R)-8 enantiomer bearing the chiral (α-methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S) alanine unit, (S)-23, (S,R)-25, (S)-31 and (S)-33, were remarkably more potent than the corresponding (R)-enantiomers...
June 19, 2017: Journal of Medicinal Chemistry
Ashley N Matthew, Jacqueto Zephyr, Caitlin J Hill, Muhammad Jahangir, Alicia Newton, Christos J Petropoulos, Wei Huang, Nese Kurt-Yilmaz, Celia A Schiffer, Akbar Ali
A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure-activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite...
June 19, 2017: Journal of Medicinal Chemistry
Revital Yefidoff-Freedman, Jing Fan, Lu Yan, Qingwen Zhang, Guillermo Rodrigo Reis Dos Santos, Sandeep Rana, Jacob I Contreras, Rupam Sahoo, Debin Wan, Jun Young, Karina Luiza Dias Teixeira, Christophe Morisseau, Jose Halperin, Bruce Hammock, Amarnath Natarajan, Peimin Wang, Michael Chorev, Bertal H Aktas
Heme-regulated inhibitor (HRI), an eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, plays critical roles in cell proliferation, differentiation, adaptation to stress, and hemoglobin disorders. HRI phosphorylates eIF2α, which couples cellular signals, including endoplasmic reticulum (ER) stress, to translation. We previously identified 1,3-diarylureas and 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific activators of HRI that trigger the eIF2α phosphorylation arm of ER stress response as molecular probes for studying HRI biology and its potential as a druggable target...
June 19, 2017: Journal of Medicinal Chemistry
Rita Nasti, Daniela Rossi, Marialaura Amadio, Alessia Pascale, M Yagiz Unver, Anna K H Hirsch, Simona Collina
RNA-binding proteins play a key role in post-transcriptional processes. Among these proteins, embryonic lethal abnormal vision (ELAV) proteins are among the best described. ELAV proteins predominantly act as positive regulators of gene expression, and their dysregulation is involved in several pathologies, such as cancer, inflammation, and neurodegenerative diseases. Only a few structurally unrelated compounds interfering with ELAV protein-mRNA complexes have been identified by applying high-throughput screening approaches...
June 19, 2017: Journal of Medicinal Chemistry
Katharina Stenzel, Alexandra Hamacher, Finn K Hansen, Christoph G W Gertzen, Johanna Senger, Viktoria Marquardt, Linda Marek, Martin Marek, Christophe Romier, Marc Remke, Manfred Jung, Holger Gohlke, Matthias U Kassack, Thomas Kurz
The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC50 values in the low μM and sub-μM range...
June 19, 2017: Journal of Medicinal Chemistry
Edwige Lorthiois, Karen Anderson, Anna Vulpetti, Olivier Rogel, Frederic Cumin, Nils Ostermann, Stefan Steinbacher, Aengus Mac Sweeney, Omar Delgado, Sha-Mei Liao, Stefan Randl, Simon Rüdisser, Solene Dussauge, Kamal Fettis, Laurence Kieffer, Andrea de Ekernez, Louis Yang, Constanze Hartwieg, Upendra A Argikar, Laura R LaBonte, Ronald Newton, Viral Kansara, Stefanie Flohr, Ulrich Hommel, Bruce Jaffee, Jürgen Maibaum
The highly specific S1 serine protease Factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of non-covalent reversible and selective human Factor D (FD) inhibitors with drug-like properties...
June 16, 2017: Journal of Medicinal Chemistry
Matteo Falsini, Lucia Squarcialupi, Daniela Catarzi, Flavia Varano, Marco Betti, Diego Dal Ben, Gabriella Marucci, Michela Buccioni, Rosaria Volpini, Teresa De Vita, Andrea Cavalli, Vittoria Colotta
In this work, we describe the identification of the 1,2,4-triazolo[4,3-a]pyrazin-3-one as a new versatile scaffold for the development of adenosine human (h) receptor antagonists. The new chemotype ensued from a molecular simplification approach applied to our previously reported 1,2,4-triazolo[4,3-a]quinoxalin-1-one series. Hence, a set of novel 8-amino-2-aryl-1,2,4-triazolopyrazin-3-one derivatives, featured by different substituents on the 2-phenyl ring (R) and at position 6 (R6), was synthesized with the main purpose of targeting the hA2A adenosine receptor (AR)...
June 16, 2017: Journal of Medicinal Chemistry
Ana Gimeno, Luis M Santos, Mobina Alemi, Josep Rivas, Daniel Blasi, Ellen Y Cotrina, Jordi Llop, Gregorio Valencia, Isabel Cardoso, Jordi Quintana, Gemma Arsequell, Jesús Jiménez-Barbero
Several strategies against Alzheimer disease (AD) are directed to target Aβ-peptides. The ability of transthyretin (TTR) to bind Aβ-peptides and the positive effect exerted by some TTR stabilizers for modulating the TTR-Aβ interaction have been previously studied. Herein, key structural features of the interaction between TTR and the Aβ(12-28) peptide (3), the essential recognition element of Aβ, have been unravelled by STD-NMR spectroscopy methods in solution. Molecular aspects related to the role of the TTR stabilizer iododiflunisal (IDIF, 5) on the TTR-Aβ complex have been also examined...
June 16, 2017: Journal of Medicinal Chemistry
Christopher J Helal, Eric P Arnold, Tracey L Boyden, Cheng Chang, Thomas A Chappie, Kimberly F Fennell, Michael D Forman, Mihaly Hajos, John F Harms, William E Hoffman, John M Humphrey, Zhijun Kang, Robin J Kleiman, Bethany L Kormos, Che-Wah Lee, Jiemin Lu, Noha Maklad, Laura McDowell, Scot Mente, Rebecca E O'Connor, Jayvardhan Pandit, Mary Piotrowski, Anne W Schmidt, Christopher J Schmidt, Hirokazu Ueno, Patrick R Verhoest, Edward X Yang
Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents...
June 16, 2017: Journal of Medicinal Chemistry
De-Ying Zeng, Guo-Tao Kuang, Shi-Ke Wang, Wang Peng, Shu-Ling Lin, Qi Zhang, Xiao-Xuan Su, Ming-Hao Hu, Honggen Wang, Jia-Heng Tan, Zhi-Shu Huang, Lian-Quan Gu, Tian-Miao Ou
The specificity of nucleic acids' binders is crucial for developing this kind of drug, especially for novel G-quadruplexes' binders. Quindoline derivatives have been developed as G-quadruplex stabilizers with good interactive activities. In order to improve the selectivity and binding affinity of quindoline derivatives as c-myc G-quadruplex binding ligands, novel triazole containing benzofuroquinoline derivatives (T-BFQs) were designed and synthesized by using the 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks...
June 16, 2017: Journal of Medicinal Chemistry
Rachel C Stewart, Amit N Patwa, Hrvoje Lusic, Jonathan D Freedman, Michel Wathier, Brian D Snyder, Ali Guermazi, Mark W Grinstaff
Contrast agents that go beyond qualitative visualization and enable quantitative assessments of functional tissue performance represent the next generation of clinically useful imaging tools. An optimized and efficient large-scale synthesis of the cationic iodinated contrast agent (CA4+) is described for imaging articular cartilage. Contrast enhanced CT (CECT) using CA4+ reveals significantly greater agent uptake of CA4+ in articular cartilage compared to similar anionic or nonionic agents, and CA4+ uptake follows Donnan Equilibrium...
June 15, 2017: Journal of Medicinal Chemistry
Jinwoo Kim, Yu Kyoung Jung, Chonsaeng Kim, Jin Soo Shin, Els Scheers, Joo-Youn Lee, Soo Bong Han, Chong-Kyo Lee, Johan Neyts, Jae-Du Ha, Young-Sik Jung
Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (6-8) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound 6g inhibited the replication of hRV-B14, A21, and A71, with respective EC50 values of 0...
June 15, 2017: Journal of Medicinal Chemistry
Alan P Kozikowski, Oluseye K Onajole, Jozef Stec, Christian Dupont, Albertus Viljoen, Matthias Richard, Tridib Chaira, Shichun Lun, William Bishai, V Samuel Raj, Diane Ordway, Laurent Kremer
Mycobacterium abscessus is a fast-growing, multidrug-resistant organism that has emerged as a clinically significant pathogen in cystic fibrosis (CF) patients. The intrinsic resistance of M. abscessus to most commonly available antibiotics seriously restricts chemotherapeutic options. Herein, we report the potent activity of a series of indolecarboxamides against M. abscessus. The lead compounds, 6 and 12, exhibited strong activity in vitro against a wide panel of M. abscessus isolates and in infected macrophages...
June 15, 2017: Journal of Medicinal Chemistry
Timothy B Durham, Jothirajah Marimuthu, James L Toth, Chin Liu, Lisa A Adams, Daniel Robert Mudra, Craig A Swearingen, Chaohua Lin, Mark G Chambers, Kannan Thirunavukkarasu, Michael R Wiley
Aggrecanase 1 and 2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of compound 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of os-teoarthritis. The projected human dose required to achieve sustained plasma levels  10 times the hADAMTS-5 IC50 is 5 mg QD.
June 14, 2017: Journal of Medicinal Chemistry
Wolfgang Albrecht, Anke Unger, Silke M Bauer, Stefan A Laufer
The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4) and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha (TNFα) release...
June 14, 2017: Journal of Medicinal Chemistry
Katarzyna Guzik, Krzysztof M Zak, Przemyslaw Grudnik, Katarzyna Magiera, Bogdan Musielak, Ricarda Törner, Lukasz Skalniak, Alexander Dömling, Grzegorz Dubin, Tad A Holak
Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number of disadvantages such as the high cost of the antibodies, their limited half-life and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors that could overcome these drawbacks is slow because of the incomplete structural information for this pathway. The first chemical PD-1/PD-L1 inhibitors have been recently disclosed by Bristol-Myers Squibb...
June 14, 2017: Journal of Medicinal Chemistry
Yameng Pei, Chunting Wang, S Frank Yan, Gang Liu
No abstract text is available yet for this article.
June 14, 2017: Journal of Medicinal Chemistry
Ludovic Peauger, Rabah Azzouz, Vincent Gembus, Mihaela-Liliana Tintas, Jana Sopková-de Oliveira Santos, Pierre Bohn, Cyril Papamicaël, Vincent Levacher
With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer's disease, we report herein a new class of donepezil-based "bio-oxidizable" prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive...
June 14, 2017: Journal of Medicinal Chemistry
Katherine L Lee, Catherine M Ambler, David R Anderson, Brian P Boscoe, Andrea G Bree, Joanne I Brodfuehrer, Jeanne S Chang, Chulho Choi, Seungwon Chung, Kevin J Curran, Jacqueline E Day, Christoph M Dehnhardt, Ken Dower, Susan E Drozda, Richard K Frisbie, Lori K Gavrin, Joel A Goldberg, Seungil Han, Martin Hegen, David Hepworth, Heidi R Hope, Satwik Kamtekar, Iain C Kilty, Arthur Lee, Lih-Ling Lin, Frank E Lovering, Michael D Lowe, John P Mathias, Heidi M Morgan, Elizabeth A Murphy, Nikolaos Papaioannou, Akshay Patny, Betsy S Pierce, Vikram R Rao, Eddine Saiah, Ivan J Samardjiev, Brian M Samas, Marina W H Shen, Julia H Shin, Holly H Soutter, Joseph W Strohbach, Peter T Symanowicz, Jennifer R Thomason, John D Trzupek, Richard Vargas, Fabien Vincent, Jiangli Yan, Christoph W Zapf, Stephen W Wright
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40)...
June 14, 2017: Journal of Medicinal Chemistry
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