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Journal of Medicinal Chemistry

Jiaul Hoque, Mohini Mohan Konai, Shanola Smitha Sequeira, Sandip Samaddar, Jayanta Haldar
More than 80% of the bacterial infections are associated with biofilm formation. To combat infections, amphiphilic small molecules have been developed as promising antibiofilm agents. However, cytotoxicity of such molecules still remains a major problem. Herein we demonstrate a concept in which antibacterial versus cytotoxic activities of cationic small molecules is tuned by spatial positioning of hydrophobic moieties while keeping positive charges constant. Compared to the molecules with more pendent hydrophobicity from positive centres (MIC = 1-4 μg/mL and HC50 = 60-65 μg/mL), molecules with more confined hydrophobicity between two centres show similar antibacterial activity but significantly less toxicity towards human erythrocytes (MIC = 1-4 μg/mL and HC50 = 805-1242 μg/mL)...
November 4, 2016: Journal of Medicinal Chemistry
Jehad Almaliti, Ayad A Al-Hamashi, Ahmed T Negmeldin, Christin L Hanigan, Lalith Perera, Mary Kay H Pflum, Robert A Casero, L M Viranga Tillekeratne
A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp3 to sp2at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole...
November 3, 2016: Journal of Medicinal Chemistry
Erik Gilberg, Swarit Jasial, Dagmar Stumpfe, Dilyana Dimova, Jürgen Bajorath
In PubChem screening assays, 466 highly promiscuous compounds were identified that were examined for known pan-assay interference compounds (PAINS) and aggregators using publicly available filters. These filters detected 210 PAINS and 67 aggregators. Compounds passing the filters included additional PAINS that were not detected, mostly due to tautomerism, and a variety of other potentially reactive compounds currently not encoded as PAINS. For a subset of compounds passing the filters, there was no evidence of potential artifacts...
November 3, 2016: Journal of Medicinal Chemistry
Dorin Toader, Fengjiang Wang, Lakshmaiah Gingipalli, Melissa Marie Vasbinder, Mark Roth, Shenlan Mao, Michael H Block, Jay Harper, Sambaiah Thota, Mei Su, Jianquo Ma, Vahe Bedian, Adeela Kamal
Herein we report structure-cytotoxicity relationships for analogs of N14-Desacetoxytubulyisn H 1. A novel synthetic approach towards 1 enabled the discovery of compounds with a range of activity. Calculated basicity of the N-terminus of tubulysins was shown to be a good predictor of cytotoxicity. The impact of structural modifications at the C-terminus of 1 upon cytotoxicity is also described. These findings will facilitate the development of new tubulysin ana-logs for the treatment of cancer.
November 3, 2016: Journal of Medicinal Chemistry
Carlotta Granchi, Flavio Rizzolio, Stefano Palazzolo, Sara Carmignani, Marco Macchia, Giuseppe Saccomanni, Clementina Manera, Adriano Martinelli, Filippo Minutolo, Tiziano Tuccinardi
Monoacylglycerol lipase (MAGL) inhibitors are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Many MAGL inhibitors are reported in literature; however, most of them showed an irreversible mechanism of action, which caused important side effects. The use of reversible MAGL inhibitors has been only partially investigated so far, mainly because of the lack of compounds with good MAGL reversible inhibition properties. In this study, starting from the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) lead compound that showed a reversible mechanism of MAGL inhibition (Ki = 8...
November 3, 2016: Journal of Medicinal Chemistry
Ling Tong, Wensheng Yu, Lei Chen, Oleg Selyutin, Michael P Dwyer, Anilkumar Gopinadhan Nair, Robert Mazzola, Jae-Hun Kim, Deyou Sha, Jingjun Yin, Rebecca Tamra Ruck, Ian W Davies, Bin Hu, Bin Zhong, Jinglai Hao, Tao Ji, Shuai Zan, Rong Liu, Sony Agrawal, Ellen Xia, Stephanie Curry, Patricia Mcmonagle, Karin Bystol, Frederick Lahser, Donna Carr, Laura Rokosz, Paul Ingravallo, Shiying Chen, Kung-I Feng, Mark Cartwright, Ernest Asante-Appiah, Joseph A Kozlowski
We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core, while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection..
November 3, 2016: Journal of Medicinal Chemistry
Pengfei Zhou, Yan Liu, Lu Zhou, Kongkai Zhu, Kechang Feng, Hao Zhang, Yuru Liang, Hualiang Jiang, Cheng Luo, Mingming Liu, Yang Wang
A series of chiral β-lactam bridged analogues (3-substituted 1,4-diaryl-2-azetidinones) of combretastatin A-4 (CA-4) were syn-thesized asymmetrically and evaluated their anti-tumor activities in vitro and in vivo. The co-crystal structure of tubulin in complex with compound 9 was determined by X-ray crystallography, which showed that 9 binds to the same site as colchicine with similar binding mode, and the absolute configuration of its C-4 was firstly identified and demonstrated critically important for their antiproliferative activities...
November 2, 2016: Journal of Medicinal Chemistry
Xin Chen, John D McCorvy, Matthew G Fischer, Kyle V Butler, Yudao Shen, Bryan L Roth, Jian Jin
Biased ligands (also known as functionally selective ligands) of G protein-coupled receptors are valuable tools for dissecting the roles of G protein-dependent and independent signaling pathways in health and disease. Biased ligands have also been increasingly pursued by the biomedical community as promising therapeutics with improved efficacy and reduced side effects compared with unbiased ligands. We previously discovered first-in-class β-arrestin-biased agonists of dopamine D2 receptor (D2R) by extensively exploring multiple regions of aripiprazole, a balanced D2R agonist...
November 2, 2016: Journal of Medicinal Chemistry
Jina Kim, Seo Yeon Woo, Chun Young Im, Eun Kyung Yoo, Seung Mi Lee, Hyo-Ji Kim, Hee-Jong Hwang, Joong-Heui Cho, Won Seok Lee, Heeseok Yoon, Shinae Kim, Oh-Bin Kwon, Hayoung Hwang, Kyung-Hee Kim, Jae-Han Jeon, Thoudam Debraj Singh, Sang Wook Kim, Sung Yeoun Hwang, Hueng-Sik Choi, In-Kyu Lee, Seong Heon Kim, Yong Hyun Jeon, Jungwook Chin, Sung Jin Cho
We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that have not only shown to be highly selective agonists for ERR, but also exhibited enhanced pharmacokinetic profile than 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERR over the ERRα, βand ERαThe in vivo pharmacokinetic profiles of 6g and 10b were further evaluated as they possessed superior in vitro ADMET profiles compared to the other compounds...
November 2, 2016: Journal of Medicinal Chemistry
Kyle V Butler, Anqi Ma, Wenyu Yu, Fengling Li, Wolfram Tempel, Nicolas Babault, Fabio Pittella-Silva, Jason Shao, Junyi Wang, Minkui Luo, Masoud Vedadi, Peter J Brown, Cheryl H Arrowsmith, Jian Jin
Selective inhibitors of protein lysine methyltransferases, including SET domain-containing protein 8 (SETD8), are highly desired, as only a fraction of these enzymes are associated with high-quality inhibitors. From our previously discovered SETD8 inhibitor, we developed a more potent analog and solved a cocrystal structure, which is the first crystal structure of SETD8 in complex with a small-molecule inhibitor. This cocrystal structure allowed the design of a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine residue near the inhibitor binding site, has an IC50 value of 804 nM, reacts with SETD8 with near-quantitative yield, and is selective for SETD8 against 28 other methyltransferases...
November 2, 2016: Journal of Medicinal Chemistry
Valentina Nieddu, Giansalvo Pinna, Irene Marchesi, Luca Sanna, Battistina Asproni, Gérard Aimè Pinna, Luigi Marco Bagella, Gabriele Murineddu
A series of novel unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles was synthetized and evaluated for their cytotoxic activity against different cancer cell lines of various origins as in vitro tumor models. Four of 12 new compounds (2b, 2h, 2j and 2l) showed growth inhibitory activity using the XTT dye assay. The most active agent, 2-(2-methyl-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-5-phenyl-1,3,4-oxadiazole, 2j, was chosen for further studies. It showed high potency against a panel of cultured human cancer cells with IC50 ranging from 0...
November 1, 2016: Journal of Medicinal Chemistry
Zi-Long Wang, Jia-Xin Pan, Jing-Jing Song, Hong-Hai Tang, Hong-Ping Yu, Xu-Hui Li, Ning Li, Ting Zhang, Run Zhang, Meng-Na Zhang, Biao Xu, Quan Fang, Rui Wang
The opioid and neuropeptide FF pharmacophore-containing chimeric peptide 0 (BN-9) was recently developed and produced potent non-tolerance forming analgesia. In this study, eleven analogs of 0 were designed and synthesized. An in vitro cAMP assay demonstrated that these analogs behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogs produced potent non-tolerance forming antinociception. Notably, 11 (DN-9) was 33-fold more potent than 0 at analgesic effects, which was mediated by μ- and κ-opioid receptors...
October 31, 2016: Journal of Medicinal Chemistry
Je Ho Ryu, Jung A Lee, Shinae Kim, Young Ah Shin, Jewon Yang, Hye Young Han, Hyun Joo Son, Yong Hyuk Kim, Joon Ho Sa, Jae-Sun Kim, Jungeun Lee, Jeeyeon Lee, Hyeung-Geun Park
A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11β-hydroxysteroid dehydrogenase type 1 was synthesized and evaluated to optimize the lead compound 9. The combination of the replacement of a pyridine ring of 9 with a pyrimidine ring and the introduction of an additional fluorine substituent at the 2-position of the phenyl ring resulted in the discovery of a potent, selective, and orally bioavailable inhibitor, 18a (SKI2852), which demonstrated no CYP and PXR liabilities, excellent PK profiles across species, and highly potent and sustainable PD activity...
October 31, 2016: Journal of Medicinal Chemistry
Cyf N Ramos-Colon, Yeon Sun Lee, Michael Vincent Remesic, Sara M Hall, Justin LaVigne, Peg Davis, Alexander J Sandweiss, Mary I McIntosh, Jessica Hanson, Tally M Largent-Milnes, Todd W Vanderah, John M Streicher, Frank Porreca, Victor J Hruby
Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the kappa opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg(7) residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg(7)]-Dyn A analogues found that Arg(7) is not a key residue and even deletion of the residue does not affect biological activities at the KOR...
October 31, 2016: Journal of Medicinal Chemistry
Wensheng Yu, Ling Tong, Bin Hu, Bin Zhong, Jinglai Hao, Tao Ji, Shuai Zan, Craig Alan Coburn, Oleg Selyutin, Lei Chen, Laura Rokosz, Sony Agrawal, Rong Liu, Stephanie Curry, Patricia Mcmonagle, Paul Ingravallo, Ernest Asante-Appiah, Shiying Chen, Joseph A Kozlowski
The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as "Z" group replacements offered good potency across all genotypes...
October 28, 2016: Journal of Medicinal Chemistry
Sebastian Bandholtz, Sarah Erdmann, Jan Lennart von Hacht, Samantha Exner, Gerd Krause, Gunnar Kleinau, Carsten Grötzinger
This study investigated the role of individual U-II amino acid positions and side chain characteristics important for U-IIR activation. A complete permutation library of 209 U-II variants was studied in an activity screen that contained single substitution variants of each position with one of the other 19 proteinogenic amino acids. Receptor activation was measured using a cell-based high-throughput fluorescence calcium mobilization assay. We generated the first complete U-II substitution map for U-II receptor activation resulting in a detailed view into the structural features required for receptor activation - accompanied by complementary information from receptor modeling and ligand docking studies...
October 28, 2016: Journal of Medicinal Chemistry
Belén Rubio-Ruiz, Jason T Weiss, Asier Unciti-Broceta
Bioorthogonal uncaging strategies have recently emerged as an experimental therapeutic approach to control drug release. Herein we report a novel masking strategy that enables to modulate the metal chelating properties of hydroxamic acid groups by bioorthogonal chemistry using Pd-functionalized resins. This novel approach allowed to devise an inactive precursor of the histone deacetylase inhibitor vorinostat that was efficiently uncaged by heterogeneous Pd catalysis in cell culture models of glioma and lung cancer...
October 27, 2016: Journal of Medicinal Chemistry
Thierry Lioux, Marc-Antoine Mauny, Alain Lamoureux, Nicolas Bascoul, Mathieu Hays, Fabienne Vernejoul, Anne-Sophie Baudru, Cédric Boularan, Justine Lopes-Vicente, Gregory Qushair, Gérard Tiraby
We describe novel STING-activating cyclic dinucleotides whose constituent nucleosides are adenosine and inosine, and that vary by ribose substitution, internucleotide linkage position and phosphate modification. In mammalian cells in vitro, some of these cAIMP analogs induce greater STING-dependent IRF and NF-κB pathway signaling than do the reference agonists for murine (DMXAA) or human (2',3'-cGAMP) STING. In human blood ex vivo, they induce type I interferons (IFNs) and pro-inflammatory cytokines: for the former, 3',3'-cAIMP (9; EC50: 6...
October 26, 2016: Journal of Medicinal Chemistry
Xingyue Ji, Jinhua Chen, Guang-Hui Zheng, Meng-Hao Huang, Lei Zhang, Jie Jin, Hong Yi, Jian-Dong Jiang, Zong-Gen Peng, Zhuo-Rong Li
There still remains a need to develop new anti-HCV agents with distinct mechanism of action (MOA) due to the occurrence of resistance to direct-acting antiviral agents (DAAs). Cajanine, a stilbenic component isolated from Cajanus cajan L., was identified as a potent HCV inhibitor by phenotypic screening in this work (EC50 = 3.17±0.75 μM). The intensive structure optimization provided significant insights into the structure-activity relationships. Furthermore, the MOA study revealed that cajanine inhibited HCV replications via down-regulating a cellular protein chondroitin sulfate N-acetylgalactosaminyltransferase 1...
October 26, 2016: Journal of Medicinal Chemistry
Travis S Hughes, Jinsai Shang, Richard Brust, Ian Mitchelle S de Vera, Jakob Fuhrmann, Claudia Ruiz, Michael D Cameron, Theodore M Kamenecka, Douglas J Kojetin
In a previous study, a co-crystal structure of PPARγ bound to 2-chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (1, T2384) revealed two orthosteric pocket binding modes attributed to a concentration-dependent biochemical activity profile. However, 1 also bound an alternate/allosteric site that could alternatively account for the profile. Here, we show ligand aggregation afflicts the activity profile of 1 in biochemical assays. However, ligand-observed fluorine (19F) and protein-observed NMR confirms 1 binds PPARγ with two orthosteric binding modes and an allosteric site...
October 26, 2016: Journal of Medicinal Chemistry
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