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Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/29350927/synthesis-and-pharmacological-characterization-of-c4%C3%AE-amide-substituted-2-aminobicyclo-3-1-0-hexane-2-6-dicarboxylates-identification-of-1s-2s-4s-5r-6s-2-amino-4-3-methoxybenzoyl-amino-bicyclo-3-1-0-hexane-2-6-dicarboxylic-acid-ly2794193-a-highly-potent-and
#1
James A Monn, Steven S Henry, Steven M Massey, David K Clawson, Qi Chen, Benjamin A Diseroad, Rajni M Bhardwaj, Shane Atwell, Frances Lu, Jing Wang, Marijane Russell, Beverly A Heinz, Xu-Shan Wang, Joan H Carter, Brian G Getman, Kofi Adragni, Lisa M Broad, Helene E Sanger, Daniel Ursu, John T Catlow, Steven Swanson, Bryan G Johnson, David B Shaw, David L McKinzie, Junliang Hao
Multiple therapeutic opportunities have been suggested for compounds capable of selective activation of metabotropic glutamate 3 (mGlu3) receptors, but small molecule tools are lacking. As part of our ongoing efforts to identify potent, selective and systemically bioavailable agonists for mGlu2 and mGlu3 receptor subtypes, a series of C4β-N-linked variants of (1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared and evaluated for both mGlu2 and mGlu3 receptor binding affinity and functional cellular responses...
January 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29350534/discovery-of-tetrahydroisoquinoline-containing-cxcr4-antagonists-with-improved-in-vitro-admet-properties
#2
Eric J Miller, Edgars Jecs, Valarie M Truax, Brooke M Katzman, Yesim A Tahirovic, Robert J Wilson, Katie M Kuo, Michelle B Kim, Huy H Nguyen, Manohar T Saindane, Huanyu Zhao, Tao Wang, Chi S Sum, Mary Ellen Cvijic, Gretchen M Schroeder, Lawrence J Wilson, Dennis C Liotta
CXCR4 is a 7-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥ 48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4+ tumor cells from immune surveillance and chemotherapeutic elimination by 1) stimulating pro-survival signaling and 2) recruiting CXCR4+ immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4+ metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated pro-survival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR4+ cancer cell metastasis...
January 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29346733/synthesis-and-structure-activity-relationship-sar-studies-of-novel-pyrazolopyridine-derivatives-as-inhibitors-of-enterovirus-replication
#3
Yanpeng Xing, Jun Zuo, Paul Krogstad, Michael E Jung
A series of novel pyrazolopyridine compounds have been designed and prepared by a general synthetic route. Their activities against the replication of poliovirus-1, EV-A71, and CV-B3 enteroviruses were evaluated. The comprehensive understanding of the Structure-Activity Relationship was obtained by utilizing the variation of four positions, namely N1, C6, C4 and linker unit. From the screened analogues, the inhibitors with the highest selectivity indices at 50% inhibition of viral replication (SI50) were those with isopropyl at the N1 position and thiophenyl-2-yl unit at C6 position...
January 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29345930/%C3%AE-amino-%C3%AE-carboxymuconate-%C3%AE%C2%B5-semialdehyde-decarboxylase-acmsd-inhibitors-as-novel-modulators-of-de-novo-nicotinamide-adenine-dinucleotide-nad-biosynthesis
#4
Roberto Pellicciari, Paride Liscio, Nicola Giacchè, Francesca De Franco, Andrea Carotti, Janet Robertson, Lucia Cialabrini, Elena Katsyuba, Nadia Raffaelli, Johan Auwerx
NAD+ has a central function in linking cellular metabolism to major cell signaling and gene regulation pathways. Defects in NAD+ homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Whilst the beneficial effects of NAD+ boosting are well established in mitochondrial fitness, metabolism, and lifespan, to date, no therapeutic enhancers of de novo NAD+ biosynthesis have been reported. Herein we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thienyl)-2-pyrimidinyl]thio]methyl]phenylacetic acid (TES-1025, 22) the first potent and selective inhibitor of human ACMSD (IC50 = 0...
January 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29342358/synthesis-and-biological-characterization-of-aryl-uracil-inhibitors-of-hepatitis-c-virus-ns5b-polymerase-discovery-of-abt-072-a-trans-stilbene-analog-with-good-oral-bioavailability
#5
John Randolph, A Chris Krueger, Pamela Donner, John K Pratt, Dachun Liu, Christopher E Motter, Todd W Rockway, Mike D Tufano, Rolf Wagner, Hock B Lim, Jill M Beyer, Rubina Mondal, Neeta S Panchal, Lynn Colletti, Yaya Liu, Gennadiy Koev, Warren M Kati, Lisa E Hernandez, David W A Beno, Kenton L Longenecker, Kent D Stewart, Emily O Dumas, Akhteruzzaman Molla, Clarence Maring
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility, and provided much better pharmacokinetic properties in preclinical species...
January 17, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29341607/in-vitro-pharmacokinetic-optimizations-of-am2-s31n-channel-blockers-led-to-the-discovery-of-slow-binding-inhibitors-with-potent-antiviral-activity-against-drug-resistant-influenza-a-viruses
#6
Yuanxiang Wang, Yanmei Hu, Shuting Xu, Yongtao Zhang, Rami Musharrafieh, Raymond Kin Hau, Chunlong Ma, Jun Wang
Influenza viruses are respiratory pathogens that are responsible for both seasonal influenza epidemics and occasional influenza pandemics. The narrow therapeutic window of oseltamivir, coupled with the emergence of drug resistance, calls for the next-generation of antivirals. With our continuous interest in developing AM2-S31N inhibitors as oral influenza antivirals, we report here the progress of optimizing the in vitro pharmacokinetic (PK) properties of AM2-S31N inhibitors. Several AM2-S31N inhibitors, including compound 10b, were discovered to have potent channel blockage, single to submicromolar antiviral activity, and favorable in vitro PK properties...
January 17, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29328660/x-ray-structures-of-target-ligand-complexes-containing-compounds-with-assay-interference-potential
#7
Erik Gilberg, Michael Gütschow, Jürgen Bajorath
Pan assay interference compounds (PAINS) have become a paradigm for compound classes that might cause artifacts in biological assays. PAINS-defining substructures are typically contained in larger compounds. We have systematically examined X-ray structures of protein-ligand complexes for compounds containing PAINS motifs. In 2874 X-ray structures, 1107 unique ligands with PAINS substructures belonging to 70 different classes were identified. PAINS most frequently detected in crystallographic ligands included a number of prominent candidates such as quinones, catechols, or Mannich bases...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29328656/design-and-synthesis-of-novel-reactive-oxygen-species-inducers-for-the-treatment-of-pancreatic-ductal-adenocarcinoma
#8
Yuting Kuang, Mario Sechi, Salvatore Nurra, Mats Ljungman, Nouri Neamati
Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29328655/identification-of-novel-coumestan-derivatives-as-polyketide-synthase-13-inhibitors-against-mycobacterium-tuberculosis
#9
Wei Zhang, Shichun Lun, Shu-Huan Wang, Xingwu Jiang, Fan Yang, Jie Tang, Abigail L Manson, Ashlee M Earl, Hendra Gunosewoyo, William R Bishai, Li-Fang Yu
Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound, whose X-ray co-crystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally-related benzofurans with the aim to improve their potency and bioavailability...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29328649/phenylthiomethyl-ketone-based-fragments-show-selective-and-irreversible-inhibition-of-enteroviral-3c-proteases
#10
Robert Schulz, Amira Atef, Daniel Becker, Franziska Gottschalk, Carolin Tauber, Stefan Wagner, Christoph Arkona, Atef A Abdel-Hafez, Hassan H Farag, Jörg Rademann, Gerhard Wolber
Lead structure discovery mainly focuses on the identification of noncovalently binding ligands. Covalent linkage, however, is an essential binding mechanism for a multitude of successfully marketed drugs although discovered by serendipity in most cases. We present a concept for the design of fragments covalently binding to proteases. Covalent linkage enables fragment binding unrelated to affinity to shallow protein binding sites and at the same time allows differentiated targeted hit verification and binding location verification through mass spectrometry...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29327929/development-of-candidates-for-pet-imaging-of-ghrelin-receptor-in-disease-design-synthesis-and-evaluation-of-fluorine-bearing-quinazolinone-derivatives
#11
Jin-Qiang Hou, Michael S Kovacs, Savita Dhanvantari, Leonard G Luyt
Molecular imaging with PET (Positron Emission Tomography) is an attractive platform for non-invasive detection and assessment of disease. The development of a PET imaging agent targeting the ghrelin receptor (growth hormone secretagogue receptor type 1a or GHS-R1a) has the potential to lead to the detection and assessment of the higher than normal expression of GHS-R1a in diseases such as prostate, breast, and ovarian cancer. To enable the development of 18F radiopharmaceuticals, we have designed and synthesized three series of quinazolinone derivatives, resulting in the identification of two compound (5i, 17) with sub-nanomolar binding affinity and one fluorine-bearing compound (10b) with picomolar binding affinity (20 pM), representing the highest binding affinity for GHS-R1a reported to date...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29323899/optimization-of-potent-and-selective-tricyclic-indole-diazepinone-myeloid-cell-leukemia-1-mcl-1-inhibitors-using-structure-based-design
#12
Subrata Shaw, Zhiguo Bian, Bin Zhao, James C Tarr, Nagarathanam Veerasamy, KyuOk Jeon, Johannes Belmar, Allison L Arnold, Stuart A Fogarty, Evan Perry, John L Sensintaffar, DeMarco V Camper, Olivia W Rossanese, Taekyu Lee, Edward T Olejniczak, Stephen W Fesik
Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1 sensitive cells...
January 11, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29323491/g-quadruplex-identification-in-the-genome-of-protozoan-parasites-points-to-naphthalene-diimide-ligands-as-new-antiparasitic-agents
#13
Efres Belmonte-Reche, Marta Martínez-García, Aurore Guédin, Michela Zuffo, Matilde Arévalo-Ruiz, Filippo Doria, Jenny Campos-Salinas, Marjorie Maynadier, Jose-Juan Lopez-Rubio, Mauro Freccero, Jean-Louis Mergny, Jose María Perez-Victoria, Juan Carlos Morales
G-quadruplexes (G4) are DNA secondary structures which take part in the regulation of gene expression. Putative G4 forming sequences (PQS) have been reported in mammals, yeast, bacteria and viruses. Here, we present PQS searches on the genomes of T. brucei, L. major and P. falciparum. We found telomeric sequences and new PQS motifs. Biophysical experiments showed that EBR1, a 29 nucleotide long highly repeated PQS in T. brucei, forms a stable G4 structure. G4 ligands based on carbohydrate conjugated naphthalene diimides (carb-NDIs) which bind G4's including hTel, could bind EBR1 with selectivity versus dsDNA...
January 11, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29323483/correction-to-synthesis-of-potent-and-selective-inhibitors-of-aldo-keto-reductase-1b10-and-their-efficacy-against-proliferation-metastasis-and-cisplatin-resistance-of-lung-cancer-cells
#14
Satoshi Endo, Shuang Xia, Miho Suyama, Yoshifumi Morikawa, Hiroaki Oguri, Dawei Hu, Yoshinori Ao, Satoyuki Takahara, Yoshikazu Horino, Yoshihiro Hayakawa, Yurie Watanabe, Hiroaki Gouda, Akira Hara, Kazuo Kuwata, Naoki Toyooka, Toshiyuki Matsunaga, Akira Ikari
No abstract text is available yet for this article.
January 11, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29320176/discovery-of-bisubstrate-inhibitors-of-nicotinamide-n-methyltransferase-nnmt
#15
Nicolas Babault, Abdellah Allali-Hassani, Fengling Li, Jie Fan, Alex Yue, Kevin Ju, Feng Liu, Masoud Vedadi, Jing Liu, Jian Jin
Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-containing compounds using the cofactor S-5'-adenosyl-L-methionine (SAM) as the methyl group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays important role in physiology and pathophysiology. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-molecule NNMT inhibitors are valuable chemical tools for testing biological and therapeutic hypotheses...
January 10, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29316397/discovery-of-potent-and-orally-bioavailable-dihydropyrazole-gpr40-agonists
#16
Jun Shi, Zhengxiang Gu, Elizabeth Anne Jurica, Ximao Wu, Lauren E Haque, Kristin N Williams, Andres S Hernandez, Zhenqiu Hong, Qi Gao, Marta Dabros, Akin H Davulcu, Arvind Mathur, Richard A Rampulla, Arun Kumar Gupta, Ramya Jayaram, Atsu Apedo, Douglas B Moore, Heng Liu, Lori K Kunselman, Edward J Brady, Jason J Wilkes, Bradley A Zinker, Hong Cai, Yue-Zhong Shu, Qin Sun, Elizabeth A Dierks, Kimberly A Foster, Carrie Xu, Tao Wang, Reshma Panemangalore, Mary Ellen Cvijic, Chunshan Xie, Gary G Cao, Min Zhou, John Krupinski, Jean M Whaley, Jeffrey A Robl, William R Ewing, Bruce Alan Ellsworth
G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro...
January 9, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29314840/development-of-stem-cell-mobilizing-agents-targeting-cxcr4-receptor-for-peripheral-blood-stem-cell-transplantation-and-beyond
#17
Chien-Huang Wu, Jen-Shin Song, Hsuan-Hao Kuan, Szu-Huei Wu, Ming-Chen Chou, Jiing-Jyh Jan, Lun Kelvin Tsou, Yi-Yu Ke, Chiung-Tong Chen, Kai-Chia Yeh, Sing-Yi Wang, Teng-Kuang Yeh, Chen-Tso Tseng, Chen-Lung Huang, Mine-Hsine Wu, Po-Chu Kuo, Chia-Jui Lee, Kak-Shan Shia
The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+ cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., 16) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug 1 (AMD3100), and thus considered a potential drug candidate for PBSCT indication...
January 9, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29313684/interfering-with-hur-rna-interaction-design-synthesis-and-biological-characterization-of-tanshinone-mimics-as-novel-effective-hur-inhibitors
#18
Leonardo Manzoni, Chiara Zucal, Danilo Di Maio, Vito G D'Agostino, Natthakan Thongon, Isabelle Bonomo, Preet Lal, Marco Miceli, Vanessa Baj, Marta Brambilla, Linda Cerofolini, Saioa Elezgarai, Emiliano Biasini, Claudio Luchinat, Ettore Novellino, Marco Fragai, Luciana Marinelli, Alessandro Provenzani, Pierfausto Seneci
The human antigen R (HuR) is an RNA-binding protein known to modulate the expression of target mRNA coding for proteins involved in inflammation, tumorigenesis and stress responses and is a valuable drug target. We previously found that Dihydrotanshinone-I (DHTS, 1) prevents the association of HuR with its RNA substrate, thus imparing its function. Herein, inspired by DHTS structure, we designed and synthesized an array of ortho-quinones (tanshinone mimics) using a function-oriented synthetic approach. Among others, compound 6a and 6n turned out to be more effective than 1, showing a nanomolar Ki and disrupting HuR binding to RNA in cells...
January 9, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29313676/synthesis-and-biological-evaluation-of-calothrixins-b-and-their-deoxygenated-analogues
#19
Bose Muthu Ramalingam, Nachiappan Dhatchana Moorthy, Somenath Roy Chowdhury, Thiyagarajan Mageshwaran, Elangovan Vellaichamy, Sourav Saha, Karthikeyan Ganesan, B Navin Rajesh, Saleem Iqbal, Hemanta Kumar Majumder, Krishnasamy Gunasekaran, Ramamoorthy Siva, Arasambattu Kannan Mohanakrishnan
A series of calothrixin B (2) analogues bearing substituents at the 'E' ring and their corresponding deoxygenated quinocarbazoles lacking quinone unit were synthesized. The cytotoxicities of calothrixins 1, 2, 15b-p and quinocarbazole analogues were investigated against nine cancer cell lines. The quinocarbazoles 21a and 25a inhibited the catalytic activity of human topoisomerase II. The plasmid DNA cleavage abilities of calothrixins 1, 2, 15b-p identified compound 15h causing DNA cleavage comparable to that of calothrixin A (1)...
January 9, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29309142/discovery-of-1-5-diphenylpyrazole-3-carboxamide-derivatives-as-potent-reversible-and-selective-monoacylglycerol-lipase-magl-inhibitors
#20
Mojgan Aghazadeh Tabrizi, Pier Giovanni Baraldi, Stefania Baraldi, Emanuela Ruggiero, Lucia De Stefano, Flavio Rizzolio, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Andrea Chicca, Margherita Lapillo, Jürg Gertsch, Clementina Manera, Marco Macchia, Adriano Martinelli, Carlotta Granchi, Filippo Minutolo, Tiziano Tuccinardi
Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol, which is implicated in many physiological processes. Beyond the possible utilization of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents, their application has encountered obstacles due to the unwanted effects caused by the irreversible inhibition of this enzyme. The possible application of reversible MAGL inhibitors has only recently been explored, mainly due to the deficiency of known compounds possessing efficient reversible inhibitory activities...
January 8, 2018: Journal of Medicinal Chemistry
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