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Journal of Medicinal Chemistry

Swarit Jasial, Erik Gilberg, Thomas Blaschke, Jürgen Bajorath
Assay interference compounds give rise to false-positives and cause substantial problems in medicinal chemistry. Nearly 500 compound classes have been designated as pan-assay interference compounds (PAINS), which typically occur as substructures in other molecules. The structural environment of PAINS substructures is likely to play an important role for their potential reactivity. Given the large number of PAINS and their highly variable structural contexts, it is difficult to study context dependence on the basis of expert knowledge...
November 13, 2018: Journal of Medicinal Chemistry
Qingqing Meng, Zengtao Wang, Jiahua Cui, Qing Cui, Jinyun Dong, Qijing Zhang, Shao-Shun Li
Cytochrome P450 1B1 (CYP1B1) was found universal expressed in various tumors. Herein, we reported near-infrared fluorescent imaging probes for tumor detection via visualizing CYP1B1. After introducing the linker to a CYP1B1 selective inhibitor we found previously, we got the resulting compound 5b which kept strong inhibition ability against CYP1B1 (IC50 = 8.7±1.2 nM) and high selectivity. Then, in vitro microscope studies and cell binding assay of probes indicated the corresponding probe 6b could specifically accumulated in CYP1B1 overexpressed colorectal cancer cell HCT-15 and showed satisfying binding affinity to target...
November 13, 2018: Journal of Medicinal Chemistry
Paulina Jakubiak, Michael Reutlinger, Patrizio Mattei, Franz Schuler, Arto Urtti, Rubén Alvarez-Sánchez
Binding of drugs to ocular melanin is a prominent biological phenomenon that affects the local pharmacokinetics and pharmacodynamics in the eye. In this work, we report on the development of in vitro and in silico tools for an early assessment and prediction of melanin binding properties of small molecules. A robust high-throughput assay has been established to study the binding of large sets of compounds to melanin. The extremely randomized trees approach was used to develop an in silico model able to predict the extent of melanin binding from the molecular properties of the compounds...
November 13, 2018: Journal of Medicinal Chemistry
Poonam Singla, Priyanka Dalal, Mahaldeep Kaur, Geeta Arya, Surendra Nimesh, Rachna Singh, Deepak B Salunke
The ever-growing risk of bacterial resistance is a critical concern. Among the various antimicrobial resistant bacterial strains, methicillin and vancomycin resistant Staphylococcus aureus are among the most dreadful, causing serious complications. On the basis of the hypothesis that microbes have reduced ability to develop resistance against membrane targeting antibiotics, bile acid oligomers having unique facially amphiphilic topologies were designed and synthesized. The oligomers with specific linkers exhibited potent and selective antibacterial activity against Gram-positive bacteria...
November 13, 2018: Journal of Medicinal Chemistry
Yepeng Luan, Jerry Li, Jean Bernatchez, Rongshi Li
Histone deacetylases (HDACs), encompassing at least eighteen members, are promising targets for anti-cancer drug discovery and development. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It has been well validated that an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment and in potentiating synergistic effects...
November 12, 2018: Journal of Medicinal Chemistry
Paul Heron, Marta Abellán-Flos, Laurent Salmon, Jurgen Sygusch
The glycolytic enzyme aldolase is an emerging drug target in diseases such as cancer and protozoan infections which are dependent on a hyperglycolytic phenotype to synthesize ATP and metabolic precursors for biomass production. To date, structural information for the enzyme in complex with phosphate-derived inhibitors has been lacking. Thus, we determined the crystal structure of mammalian aldolase in complex with naphthalene 2,6-bisphosphate (1) that served as a template for the design of bisphosphonate-based inhibitors, namely 2-phosphate-naphthalene 6-bisphosphonate (2), 2-naphthol 6-bisphosphonate (3), and 1-phosphate-benzene 4-bisphosphonate (4)...
November 12, 2018: Journal of Medicinal Chemistry
Antonella Messore, Valentina Noemi Madia, Luca Pescatori, Francesco Saccoliti, Valeria Tudino, Alessandro De Leo, Martina Bortolami, Daniela De Vita, Luigi Scipione, Federico Pepi, Roberta Costi, Silvia Rivara, Laura Scalvini, Marco Mor, Fabiana Fosca Ferrara, Emiliano Pavoni, Giuseppe Roscilli, Giuliana Cassinelli, Ferdinando M Milazzo, Gianfranco Battistuzzi, Roberto Di Santo, Giuseppe Giannini
Heparanase is the only mammalian endo-β-D-glucuronidase involved in a variety of major diseases. Up-regulation of heparanase expression increases tumor size, angiogenesis and metastasis, representing a validated target in anticancer field. To date only few small molecule inhibitors have been described but none has got through preclinical development. Previously we explored 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives as anti-heparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors...
November 9, 2018: Journal of Medicinal Chemistry
George Stuart Cockerill, James Good, Neil Mathews
Respiratory syncytial virus (RSV) is a globally prevalent viral infection with limited treatment options which hospitalizes millions each year. Treatment options have been limited to Palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and Ribavirin with very limited efficacy and significant safety concerns. This perspective surveys the range of direct acting antiviral agents (DAAs) that target key steps in the viral life cycle. A number of approaches to DAAs has produced landmark clinical studies over the last few years, notably in fusion and nucleoside inhibitors and an update of the clinical status of these compounds is provided...
November 9, 2018: Journal of Medicinal Chemistry
Benjamin Jeffries, Zhong Wang, Jerome Graton, Simon David Holland, Thomasin Brind, Ryan David Robert Greenwood, Jean-Yves Le Questel, James S Scott, Elisabetta Chiarparin, Bruno Linclau
When optimizing the bioactivity and pharmaco-kinetic properties of a drug candidate, fluorination and lipophilicity control are common medicinal chemistry strategies. Aliphatic fluorination often reduces the lipophilicity (logP), but polyfluoroalkyl groups typically increase lipophilicity. Hence the identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off target selectivity...
November 9, 2018: Journal of Medicinal Chemistry
Atwood K Cheung, Brian Hurley, Ryan Kerrigan, Lei Shu, Donovan N Chin, Yiping Shen, Gary O'Brien, Moo Je Sung, Ying Hou, Jake Axford, Emma Cody, Robert Sun, Aleem Fazal, Ronald C Tomlinson, Monish Jain, Lin Deng, Keith Hoffmaster, Cheng Song, Mailin Van Hoosear, Youngah Shin, Rebecca Servais, Christopher S Towler, Marc Hild, Daniel Curtis, William F Dietrich, Lawrence G Hamann, Karin Briner, Karen S Chen, Dione Kobayashi, Rajeev Sivasankaran, Natalie A Dales
Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists, however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070 / branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA...
November 8, 2018: Journal of Medicinal Chemistry
David Heidenreich, Moses Moustakim, Jurema Schmidt, Daniel Merk, Paul E Brennan, Oleg Fedorov, Apirat Chaikuad, Stefan Knapp
Lysine acetylation is an epigenetic mark that is principally recognized by bromodomains and recently structurally diverse YEATS domains also emerged as readers of lysine acetyl/acylations. Here we present a crystallography-based strategy and the discovery of fragments binding to the ENL YEATS domain, a potential drug target. Crystal structures combined with synthetic efforts led to the identification of a sub-micromolar binder, providing first starting points for the development of chemical probes for this reader domain family...
November 8, 2018: Journal of Medicinal Chemistry
Clémence Cheignon, Emmanuelle Cordeau, Nolween Prache, Sonia Cantel, Jean Martinez, Gilles Subra, Carine Arnaudguilhem, Brice Bouyssiere, Christine Enjalbal
In the search for an alternative strategy to the radioactivity measurement conventionally performed to probe receptor-ligand interactions in pharmacological assays, we demonstrated that selenium labeling of the studied ligand combined with elemental mass spectrometry was as efficient and robust as the reference method but devoid of its environmental and health hazards. The proof-of-concept was illustrated on two GPCR receptors, vasopressin (V1A ) and cholecystokinin B (CCK-B), involving peptides as endogenous ligands...
November 8, 2018: Journal of Medicinal Chemistry
Tobias J Hauke, Thomas Wein, Georg Höfner, Klaus T Wanner
This study describes the screening of dynamic combinatorial libraries based on nipecotic acid as core structure with substituents attached to the 5- instead of the common 1-position for the search of novel inhibitors of the GABA transporter GAT1. The generated pseudostatic hydrazone libraries included a total of nearly 900 compounds and were screened for their binding affinities toward GAT1 in competitive mass spectrometry (MS) based Binding Assays. Characterization of the hydrazones with the highest affinities (with cis-configured rac-16gf bearing a 5-(1-naphthyl)furan-2-yl residue and a four atom spacer being the most potent) in binding and uptake experiments revealed an allosteric interaction at GAT1, which was not reported for any other nipecotic acid derivative up to now...
November 8, 2018: Journal of Medicinal Chemistry
Sanil Bhatia, Viktoria Krieger, Michael Groll, Jeremy D Osko, Nina Reßing, Heinz Ahlert, Arndt Borkhardt, Thomas Kurz, David W Christianson, Julia Hauer, Finn K Hansen
Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5...
November 8, 2018: Journal of Medicinal Chemistry
Geetika Dhanda, Paramita Sarkar, Sandip Samaddar, Jayanta Haldar
Vancomycin, a natural glycopeptide antibiotic, was used as the antibiotic of last resort for the treatment of multidrug-resistant Gram-positive bacterial infections. However, almost thirty years after its use, resistance to vancomycin was first reported in 1986 in France. This became a major health concern and alternative treatment strategies were urgently needed. New classes of molecules, including semi-synthetic antibacterial compounds and newer generations of the previously used antibiotics were developed...
November 7, 2018: Journal of Medicinal Chemistry
Xiaoyun Lu, Hao Chen, Adam V Patterson, Jeff Bruce Smaill, Ke Ding
Hepatocellular Carcinoma (HCC) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Aberrant fibroblast growth factor 19 (FGF19) signaling through fibroblast growth factor receptor 4 (FGFR4) has been identified as an oncogenic driver for a subset of patients with HCC. FGFR4 is therefore a promising target for the treatment of HCC harboring aberrant FGF19-FGFR4 signaling and several FGFR4 inhibitors have advanced to clinical trial. In this review, we summarize the latest developments in FGFR4 inhibitors, including the known pharmacophores, their binding mode, selectivity and clinical implications, as well as the optimization strategy of introducing an acrylamide into a known pan-FGFR inhibitor targeting Cys552 of FGFR4 to provide selective covalent FGFR4 inhibitors...
November 7, 2018: Journal of Medicinal Chemistry
Francesco Bavo, Susanna Pucci, Francesca Fasoli, Carmen Lammi, Milena Moretti, Vanessa Mucchietto, Donatella Lattuada, Paola Viani, Clara de Palma, Roberta Budriesi, Irene Corradini, Cheryl Dowell, J Michael McIntosh, Francesco Clementi, Cristiano Bolchi, Cecilia Gotti, Marco Pallavicini
Adenocarcinoma and glioblastoma cell lines express alpha7 and alpha9-alpha10-containing nAChRs, whose activation promotes tumour cells growth. On these cells, the triethylammoniumethyl ether of 4-stilbenol MG624, a known selective antagonist of alpha7 and alpha9-alpha10 nAChRs, has antiproliferative activity. The structural analogy of MG624 with the mitocan RDM-4'BTPI, triphenylphosphoniumbutyl ether of pterostilbene, suggested us that molecular hybridisation among their three substructures (stilbenoxy residue, alkylene linker and terminal onium) and elongation of the alkylene linker might result in novel antitumour agents with higher potency and selectivity...
November 7, 2018: Journal of Medicinal Chemistry
Bohdan Waszkowycz, Kate M Smith, Alison E McGonagle, Allan M Jordan, Ben Acton, Emma Fairweather, Louise A Griffiths, Niall Hamilton, Nicola Hamilton, James Hitchin, Colin P Hutton, Dominic James, Clifford D Jones, Stuart Jones, Daniel P Mould, Helen Small, Alexandra Stowell, Julie Tucker, Ian Waddell, Donald Ogilvie
DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design...
November 7, 2018: Journal of Medicinal Chemistry
Thuy Le, Abhijit Kundu, Atanu Ghoshal, Nghi Nguyen, Sarah Preston, Yaqing Jiao, Banfeng Ruan, Lian Xue, Fei Huang, Jennifer Keiser, Andreas Hofmann, Bill Chang, Jose Garcia-Bustos, Abdul Jabbar, Timothy N C Wells, Michael J Palmer, Robin B Gasser, Jonathan B Baell
A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 µM. Medicinal chemistry optimization targeted modifications on the left-hand side, middle section and right-hand side of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0...
November 7, 2018: Journal of Medicinal Chemistry
Gyles E Cozier, Lauren B Arendse, Sylva L Schwager, Edward D Sturrock, K Ravi Acharya
Omapatrilat was designed as a vasopeptidase inhibitor with dual activity against the zinc metallopeptidases angiotensin-1 converting enzyme (ACE) and neprilysin (NEP). ACE has two homologous catalytic domains (nACE and cACE), which exhibit different substrate specificities. Here, we report high-resolution crystal structures of omapatrilat in complex with nACE and cACE and show omapatrilat has subnanomolar affinity for both domains. The structures show nearly identical binding interactions for omapatrilat in each domain, explaining the lack of domain selectivity...
November 7, 2018: Journal of Medicinal Chemistry
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