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Journal of Medicinal Chemistry

Marina Sagnou, Barbara Mavroidi, Antonio Shegani, Maria Paravatou-Petsotas, Catherine P Raptopoulou, Vassilis Psycharis, Ioannis Pirmettis, Minas S Papadopoulos, Maria Pelecanou
The synthesis and evaluation of three novel 99m Tc complexes (99m Tc-1 - 99m Tc-3), and their corresponding Re complexes (Re-1 - Re-3) in which the phenyl ring of 2-phenylbenzothiazole or 2-phenylbenzimidazole is replaced by the cyclopentadienyl tricarbonyl [Cp 99m Tc(CO)3 ] core, is reported. Both 99m Tc and Re complexes were prepared from the corresponding ferrocenyl derivatives and the Re complexes were fully characterized by elemental analysis, spectroscopic methods and X-ray crystallography. The complexes exhibit effective in vitro binding to β-amyloid (Aβ) plaques and fibrils, inhibit Aβ fibril formation, significantly reduce Aβ-induced cytotoxicity and ROS production in neuronal cell cultures...
February 15, 2019: Journal of Medicinal Chemistry
Patrik Wolle, Julia Hardick, Shane J F Cronin, Julian Engel, Matthias Baumann, Jonas Lategahn, Josef Penninger, Daniel Rauh
The protein kinase MKK7 is linked to neuronal development and the onset of cancer. The field, however, lacks high-quality functional probes that would allow for the dissection of its detailed functions. Against this background, we describe an effective covalent inhibitor of MKK7 based on the pyrazolopyrimidine scaffold.
February 15, 2019: Journal of Medicinal Chemistry
Christopher R M Asquith, Benedict-Tilman Berger, Jing Wan, James M Bennett, Stephen Joseph Capuzzi, Daniel J Crona, David Drewry, Michael P East, Jonathan M Elkins, Oleg Fedorov, Paulo H Godoi, Debra M Hunter, Stefan Knapp, Susanne Müller, Chad D Torrice, Carrow Iona Wells, Henry Shelton Earp, Tim Willson, William Zuercher
We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with a structurally-related negative control SGC-GAK-1N (14). 11 was highly selective in an in vitro kinome-wide screen, but cellular engagement assays defined RIPK2 as a collateral target. We identified 18 as a potent RIPK2 inhibitor lacking GAK activity. Together, this chemical probe set can be used to interrogate GAK cellular biology.
February 15, 2019: Journal of Medicinal Chemistry
Federica Giordani, Abedawn I Khalaf, Kirsten Gillingwater, Jane C Munday, Harry P de Koning, Colin J Suckling, Michael P Barrett, Fraser J Scott
Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa due to its huge impact on livestock health. Existing therapies including those based upon Minor Groove Binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places due to the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT, Trypanosoma congolense and T...
February 14, 2019: Journal of Medicinal Chemistry
Pek Yoke Chong, J Brad Shotwell, John F Miller, Daniel J Price, Andy Maynard, Christian Voitenleitner, Amanda Mathis, Shawn Williams, Jeffrey Pouliot, Katrina Creech, Feng Wang, Jing M Fang, Huichang Zhang, Vincent Tai, Elizabeth Turner, Kristen M Kahler, Renae Crosby, Andrew J Peat
We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which a N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein we describe second generation NS5B inhibitors including GSK8175 (49), a sulfonamide-N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons...
February 14, 2019: Journal of Medicinal Chemistry
Jacob Krall, Francesco Bavo, Christina B Falk-Petersen, Claus Hatt Jensen, Julie Olsson Nielsen, Yongsong Tian, Valeria Anglani, Kenneth Thermann Kongstad, Louise Piilgaard, Birgitte Nielsen, David E Gloriam, Jan Kehler, Anders Jensen, Kasper Harpsøe, Petrine Wellendorph, Bente Frølund
Gabazine, a GABAA receptor antagonist, has previously been reported to inhibit the binding of [3H]NCS-382, a representative ligand of the high-affinity binding site for the neuroactive substance GHB. We herein report a study on the structural determinants of gabazine for binding to i) the orthosteric binding site of the GABAA receptor and ii) the high-affinity GHB binding site. Expanding the structural diversity of available ligands for the high-affinity GHB binding sites, this study identified 2-(imidazo[1,2-b]pyridazin-2-yl)acetic acid as a novel ligand-scaffold leading to analogs with relatively high affinity (Ki 0...
February 14, 2019: Journal of Medicinal Chemistry
Suhui Yang, Andrea Shergalis, Dan Lu, Anahita Kyani, Ziwei Lu, Mats Ljungman, Nouri Neamati
Protein disulfide isomerase (PDI) is responsible for nascent protein folding in the endoplasmic reticulum (ER) and is critical for glioblastoma survival. To improve the potency of lead PDI inhibitor BAP2 ((E)-3-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzonitrile), we designed and synthesized 67 novel analogues. We determined that PDI inhibition relied on the A ring hydroxyl group of the chalcone scaffold and cLogP increase in the sulfonamide chain improved potency. Docking studies revealed that BAP2 and analogues bind to His256 in the b' domain of PDI, and mutation of His256 to Ala abolishes BAP2 analogue activity...
February 13, 2019: Journal of Medicinal Chemistry
Ciro Milite, Alessandra Feoli, John R Horton, Donatella Rescigno, Alessandra Cipriano, Vincenzo Pisapia, Monica Viviano, Giacomo Pepe, Giorgio Amendola, Ettore Novellino, Sandro Cosconati, Xiaodong Cheng, Sabrina Castellano, Gianluca Sbardella
Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of non-quinazoline inhibitors of H3K9-specific methyltransferases G9a and GLP have been reported. Herein we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the under-investigated 2-alkyl-5-amino- and 2-aryl-5-amino-substituted 3H-benzo[e][1,4]diazepine scaffold. Our research efforts yielded the identification of compound 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNMT1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both PAMPA and PAMPA-BBB assays and, therefore, might potentially be a better candidate for animal studies...
February 12, 2019: Journal of Medicinal Chemistry
Jie Tu, Zhuang Li, Yanjuan Jiang, Changjin Ji, Guiyan Han, Yan Wang, Na Liu, Chunquan Sheng
Clinical treatment of cryptococcal meningitis (CM) remains a significant challenge due to the lack of effective and safe drug therapies. Developing novel CM therapeutic agents with novel chemical scaffolds and new modes of action is of great importance. Herein, new β-hexahydrocarboline derivatives were shown to possess potent anticryptococcal activities. In particular, compound A4 showed potent in vitro and in vivo anticryptococcal activity with good metabolic stability and BBB permeability. Compound A4 was orally active and could significantly reduce brain fungal burdens in a murine model of CM...
February 12, 2019: Journal of Medicinal Chemistry
Yasushi Hattori, Kazunobu Aoyama, Jun Maeda, Naoto Arimura, Yasuko Takahashi, Masako Sasaki, Masayuki Fujinaga, Chie Seki, Yuji Nagai, Kazunori Kawamura, Tomoteru Yamasaki, Ming-Rong Zhang, Makoto Higuchi, Tatsuki Koike
Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase involved in endocannabinoid and inflammatory signaling. Positron-emission tomography (PET) imaging of MAGL serves to validate target engagement of therapeutic MAGL inhibitors as well as to investigate MAGL levels under normal and disease conditions. However, PET radioligands with reversible binding kinetics for MAGL, which allow quantitative assessment of MAGL, are hitherto unavailable. In this study, we designed and synthesized fluoro-containing PET probes starting from a recently identified piperazinyl pyrrolidine-2-one derivative with reversible binding to MAGL...
February 12, 2019: Journal of Medicinal Chemistry
Bidyadhar Sethy, Chung-Fan Hsieh, Ta-Jen Lin, Po-Yuan Hu, Yu-Li Chen, Chia-Yi Lin, Sung-Nain Tseng, Jim-Tong Horng, Pei-Wen Hsieh
Influenza A viruses (IAVs) have caused worldwide epidemics and pandemics by reassortment and generation of drug-resistant mutants, which renders antivirals and current vaccinations no longer usable. In this study, an itaconic acid derivative 1 was identified from a chemical library of 20,000 compounds by performing a cell-based screening assay as a lead agent exhibiting anti-influenza A activity. Accordingly, a series of itaconic acid derivatives were designed and synthesized by adopting a rational design strategy to obtain more potent anti-influenza agents...
February 12, 2019: Journal of Medicinal Chemistry
Jiajun Wang, Jing Song, Zhanyi Yang, Shiqi He, Yi Yang, Xingjun Feng, Xiujing Dou, Anshan Shan
Poor proteolytic resistance is an urgent problem to be solved in the clinical application of AMPs, yet common solutions, such as complicated chemical modifications and utilization of D-amino acids, greatly increase the difficulty and cost of producing AMPs. In this work, a set of novel peptides was synthesized base on an anti-trypsin/chymotrypsin hydrolytic peptide structure unit (XYPX)n (X represents I, L and V; Y represents R and K), which was designed using a systematic natural amino acid arrangement. Of these peptides, 16 with 7 repeat units had the highest average selectivity index (GMSI=99...
February 11, 2019: Journal of Medicinal Chemistry
Dennis Bensinger, Daniel Stubba, Anjali Cremer, Vanessa Kohl, Theresa Waßmer, Johanna Stuckert, Victoria Engemann, Kimberly Stegmaier, Katja Schmitz, Boris Schmidt
The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually the discovery of new irreversible kinase inhibitors occurs serendipitously showing that efficient rational approaches for the rapid discovery of new drugs are needed. Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of the FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia (AML). A virtual screening library was designed to target the highly conserved Cys828 residue preceding the DFG motif by modification of reported reversible inhibitors with chemically reactive groups...
February 11, 2019: Journal of Medicinal Chemistry
Katlyn A Fleming, Katie T Freeman, Mike D Powers, Radleigh G Santos, Ginamarie Debevec, Marc A Giulianotti, Richard A Houghten, Skye R Doering, Clemencia Pinilla, Carrie Haskell-Luevano
The centrally expressed melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are established targets to treat diseases of positive and negative energy homeostasis. We previously reported (J. Med. Chem. 60:4342 2017) mixture-based positional scanning approaches to identify dual MC3R agonist and MC4R antagonist tetrapeptides. Herein, 46 tetrapeptides were chosen for MC3R agonist screening selectivity profiles, synthesized, and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors...
February 11, 2019: Journal of Medicinal Chemistry
Johannes Popow, Heribert Arnhof, Gerd Bader, Helmut Berger, Alessio Ciulli, David Covini, Christian Dank, Teresa Gmaschitz, Peter Greb, Jale Karolyi-Oezguer, Manfred Koegl, Darryl McConnell, Mark Pearson, Maria Rieger, Jörg Rinnenthal, Vanessa Roessler, Andreas Schrenk, Markus Spina, Steffen Steurer, Nicole Trainor, Elisabeth Traxler, Corinna Wieshofer, Andreas Zoephel, Peter Ettmayer
The focal adhesion tyrosine kinase (PTK2) is often over-expressed in human hepatocellular carcinoma (HCC) and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here we present two highly selective and functional PTK2 PROTACs utilizing VHL and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC50 of 30 nM to > 80 % across a panel of eleven HCC cell lines...
February 9, 2019: Journal of Medicinal Chemistry
Serenella Medici, Massimiliano Francesco Peana, Valeria Marina Nurchi, Maria Antonietta Zoroddu
Silver has no biological role and it is particularly toxic to lower organisms. Although several silver formulations employed in medicine in the past century are prescribed and sold to treat certain medical conditions, most of the compounds, including those showing outstanding properties as antimicrobial or anticancer agents, are still in early stages of assessment, that is, in vitro studies, and may not make it to clinical trials. Unlike other heavy metals, there is no evidence that silver is a cumulative poison, but its levels can build up in the body tissues after prolonged exposure leading to undesired effects...
February 8, 2019: Journal of Medicinal Chemistry
Brian H White, Kerry Whalen, Kristina Kriksciukaite, Rossitza G Alargova, Tsun Au Yeung, Patrick Bazinet, Adam Hale Brockman, Michelle Dupont, Haley Oller, Charles-Andre Lemelin, Patrick Lim Soo, Benoit Moreau, Samantha Perino, James M Quinn, Gitanjali Sharma, Rajesh Shinde, Beata Sweryda-Krawiec, Richard Wooster, Mark T Bilodeau
Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized upon binding to the receptor and linking a toxic payload to an SSTR2 agonist is a potential method to kill SSTR2-expressing tumor cells. Herein we describe our efforts towards an efficacious SSTR2-targeting cytotoxic conjugate; examination of different SSTR2 targeting ligands, conjugation sites, and payloads led to the discovery of 22 (PEN-221), a conjugate consisting of microtubule-targeting agent DM1 linked to the C-terminal side chain of Tyr3-octreotate...
February 8, 2019: Journal of Medicinal Chemistry
Weronika Kotkowiak, Jesper Wengel, Chris J Scotton, Anna Pasternak
RE31 is a 31-nt DNA aptamer, consisting of the G quadruplex and a duplex domain, which is able to effectively prolong thrombin time. In this paper, we report on our investigations into the influence of certain modified nucleotide residues on thermal stability, folding topology and biological properties of RE31. In particular, the effect of single incorporation of canonical nucleosides in UNA, LNA or β-L-RNA series, was evaluated. The studies presented herein show that all modified residues can efficiently modulate G-quadruplex thermal and biological stability - and that the effect is strongly position dependent...
February 8, 2019: Journal of Medicinal Chemistry
Weiyang Dai, Soma Samanta, Ding Xue, Elyse M Petrunak, Jeanne A Stuckey, Yanyan Han, Duxin Sun, Yong Wu, Nouri Neamati
Using reported glutathione S-transferase omega 1 (GSTO1-1) co-crystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 µM), compound 18 was synthesized and co-crystalized with GSTO1. Modification on the amide moiety of hit compound 10 significantly increased the GSTO1-1 inhibitory potency. We solved the co-crystal structures of new derivatives, 37 and 44, bearing amide side chain bound to GSTO1...
February 8, 2019: Journal of Medicinal Chemistry
Guanglin Luo, Ling Chen, Amy Easton, Amy Newton, Clotilde Bourin, Eric Shields, Kathy Mosure, Matthew G Soars, Ronald J Knox, Michele Matchett, Rick L Pieschl, Debra J Post-Munson, Shuya Wang, James Herrington, John Graef, Kimberly Newberry, Digavalli V Sivarao, Arun Senapati, Linda J Bristow, Nicholas A Meanwell, Lorin A Thompson, Carolyn Dzierba
No abstract text is available yet for this article.
February 8, 2019: Journal of Medicinal Chemistry
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