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A Potent and Selective Human Prostaglandin F (FP) Receptor Antagonist (BAY-6672) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF).

Hartmut Beck, Tobias Thaler, Daniel Meibom, Mark Meininghaus, Hannah Joerissen, Lisa Dietz, Carsten Terjung, Michaela Bairlein, Clemens-Jeremias vonBuehler, Sonja Anlauf, Chantal Fuerstner, Timo Stellfeld, Dirk Schneider, Kersten Matthias Gericke, Thomas Buyck, Kai Dr Lovis, Uwe Muenster, Johanna Anlahr, Elisabeth Kersten, Guillaume Levilain, Virginia Marossek, Raimund Kast,

Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well tolerated anti-fibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expressed in the lung ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Transthyretin Amyloidogenesis Inhibitors: From Discovery to Current Developments.

Takeshi Yokoyama, Mineyuki Mizuguchi,

Transthyretin (TTR) is a homotetrameric protein in human plasma. The dissociation of the TTR tetramer and misfolding of the TTR monomer result in the formation of amyloid fibrils. Hereditary TTR amyloidosis is characterized by the extracellular deposition of amyloid fibrils containing TTR variants. The development of small molecules that kinetically ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry.

Patrick Mäder, Lars Kattner,

Sulfoximines have been largely disregarded in medicinal chemistry for a long time. However, recently, they have risen to the apparent level of stardom on the drug discovery scene. Considering the outstanding properties of sulfoximines, this versatile functional group has advanced to implementation in several drug discovery programs. Currently, this fashionable ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint.

Magdalena Konieczny, Bogdan Musielak, Justyna Kocik, Lukasz Skalniak, Dominik Sala, Miroslawa Czub, Katarzyna Magiera-Mularz, Ismael Rodriguez, Maja Myrcha, Malgorzata Stec, Maciej Siedlar, Tad A Holak, Jacek Plewka,

Immune checkpoint blockade is one of the most promising strategies of cancer immunotherapy. However, unlike classical targeted therapies, it is currently solely based on expensive monoclonal antibodies, which often inflict immune-related adverse events. Herein, we propose a novel small-molecule inhibitor targeted at the most clinically relevant immune checkpoint, PD-1/PD-L1. The ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.

Joanna Sniecikowska, Monika Gluch-Lutwin, Adam Bucki, Anna Więckowska, Agata Siwek, Magdalena Jastrzebska-Wiesek, Anna Partyka, Daria Wilczyńska, Karolina Pytka, Gniewomir Latacz, Katarzyna Przejczowska-Pomierny, Elżbieta Wyska, Anna Wesołowska, Maciej Pawłowski, Adrian Newman-Tancredi, Marcin Kolaczkowski,

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that ... Read more >>

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[2020, :]

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Self-adjuvanting cancer vaccines from conjugation-ready lipid A analogues and synthetic long peptides.

Niels Reintjens, Elena Tondini, Ana R de Jong, Nico J Meeuwenoord, Fabrizio Chiodo, Evert Peterse, Herman S Overkleeft, Dmitri V Filippov, Gijsbert A van der Marel, Ferry Ossendorp, Jeroen D C Codée,

Self-adjuvanting vaccines, wherein an antigenic peptide is covalently bound to an immunostimulating agent, have been shown to be promising tools for immunotherapy. Synthetic Toll-like receptor (TLR) ligands are ideal adjuvants for covalent linking to peptides or proteins. We here introduce a conjugation-ready TLR4-ligand, CRX-527, a potent powerful lipid A analogue, ... Read more >>

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[2020, :]

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Synthesis, structure-activity relationship and antimalarial efficacy of 6-chloro-2-arylvinylquinolines.

Guang Huang, Claribel Murillo Solano, Joel Melendez, Justin Shaw, Jennifer Collins, Robert Banks, Arash Keshavarzi Arshadi, Rachasak Boonhok, Hui Min, Jun Miao, Debopam Chakrabarti, Yu Yuan,

There is an urgent need to develop new efficacious antimalarials to address the emerging drug-resistant clinical cases. Our previous phenotypic screening identified styrylquinoline UCF501 as a promising antimalarial compound. To optimize UCF501, we herein report a detailed structure-activity relationship study of 2-arylvinylquinolines, leading to the discovery of potent, low nanomolar ... Read more >>

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[2020, :]

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Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers.

Chaoguo Cao, Jie Yang, Yong Chen, Peiting Zhou, Yingwei Wang, Wu Du, Lifeng Zhao, Yuanwei Chen,

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Identification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[11C]methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu2).

Tomoteru Yamasaki, Xiaofei Zhang, Katsushi Kumata, Yiding Zhang, Xiaoyun Deng, Masayuki Fujinaga, Zhen Chen, Wakana Mori, Kuan Hu, Hidekatsu Wakizaka, Akiko Hatori, Lin Xie, Masanao Ogawa, Nobuki Nengaki, Richard Van, Yihan Shao, Douglas J Sheffler, Nicholas D P Cosford, Steven H Liang, Ming-Rong Zhang,

Metabotropic glutamate receptor 2 (mGlu2) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu2, we identified new candidates 5a-i that are potent negative allosteric modulators (NAMs) of mGlu2. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide (5i, also named as ... Read more >>

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[2020, :]

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Discovery of Novel Pyrazolo[3,4-b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension.

Liqing Hu, Lijun Li, Qi Chang, Songsen Fu, Jia Qin, Zhuo Chen, Xiaohui Li, Qinglian Liu, Gaoyun Hu, Qianbin Li,

Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages ... Read more >>

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[2020, :]

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Development of PSMA-1007-Related Series of 18F-Labeled Glu-Ureido-Type PSMA Inhibitors.

Jens Cardinale, Mareike Roscher, Martin Schäfer, Max Geerlings, Martina Benešová, Ulrike Bauder-Wüst, Yvonne Remde, Matthias Eder, Zora Nováková, Lucia Motlová, Cyril Barinka, Frederik L Giesel, Klaus Kopka,

In recent years, a number of drugs targeting the prostate-specific membrane antigen (PSMA) have become important tools in the diagnosis and treatment of prostate cancer. In the present work, we report on the synthesis and preclinical evaluation of a series of 18F-labeled PSMA ligands for diagnostic application based on the ... Read more >>

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[2020, :]

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Discovery and Development of SPR519 as a Potent, Selective, and Orally Bioavailable Inhibitor of PI3Kα and mTOR Kinases for the Treatment of Solid Tumors.

Dinesh Mahajan, Somdutta Sen, Bilash Kuila, Amit Sharma, Reena Arora, Milind Sagar, Amal Ray Mahapatra, Lalita Babasaheb Gawade, Sundeep Dugar,

Herein, we report the identification and preclinical profile of a lead compound 10, (SPR519) as an equally potent dual inhibitor of PI3Kα and mTOR kinases. SPR519 exhibits an EC50 of low sub-micromolar range among various tested cancer cell lines such as A2780 (0.23 μM), PC3 (0.48 μM), and SKOV3 (0.50 ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Systematic Study of the Glutathione (GSH) Reactivity of N-Phenylacrylamides: 2. Effects of Acrylamide Substitution.

Adam Birkholz, David J Kopecky, Laurie P Volak, Michael D Bartberger, Yuping Chen, Chris Tegley, Tara L Arvedson, John D McCarter, Christopher H Fotsch, Victor J Cee,

A comprehensive understanding of structure-reactivity relationships is critical to the design and optimization of cysteine-targeted covalent inhibitors. Herein we report glutathione (GSH) reaction rates for N-phenyl acrylamides with varied substitutions at the - and - positions of the acrylamide moiety. We find that the GSH reaction rates can generally be ... Read more >>

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[2020, :]

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Therapeutic Exploitation of GPR18: Beyond the Cannabinoids?

Paula Morales, Ana Lago-Fernandez, Dow P Hurst, Noori Sotudeh, Eugen Brailoiu, Patricia H Reggio, Mary E Abood, Nadine Jagerovic,

GPR18 is a G-protein-coupled receptor that belongs to the orphan class A family. Even though it shares low sequence homology with the cannabinoid receptors CB1R and CB2R, a growing body of research suggests its relationship with the endocannabinoid system, not only because it is able to recognize cannabinoid ligands but ... Read more >>

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[2020, :]

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Discovery of 9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one (GLPG1205), a Unique GPR84 Negative Allosteric Modulator Undergoing Evaluation in a Phase II Clinical Trial.

Frédéric Labéguère, Sonia Dupont, Luke Alvey, Florilène Soulas, Gregory Newsome, Amynata Tirera, Vanessa Quenehen, Thi Thu Trang Mai, Pierre Deprez, Roland Blanqué, Line Oste, Sandrine Le Tallec, Steve De Vos, Annick Hagers, Ann Vandevelde, Luc Nelles, Nele Vandervoort, Katja Conrath, Thierry Christophe, Ellen van der Aar, Emanuelle Wakselman, Didier Merciris, Céline Cottereaux, Cécile da Costa, Laurent Saniere, Philippe Clement-Lacroix, Laura Jenkins, Graeme Milligan, Stephen Fletcher, Reginald Brys, Romain Gosmini,

GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of GPR84 (PBI-4050) that displays relatively low potency and selectivity, a clear need exists for an improved modulator. Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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A Turing test for molecular generators.

Jacob T Bush, Peter Pogány, Stephen D Pickett, Mike Barker, Andrew Baxter, Sebastien Campos, Anthony W J Cooper, David Jonathan Hirst, Graham Inglis, Alan Nadin, Vipulkumar K Patel, Darren Poole, John Pritchard, Yoshiaki Washio, Gemma White, Darren Green,

Machine learning approaches promise to accelerate and improve success rates in medicinal chemistry programmes by more effectively leveraging available data to guide molecular design. A key step of an automated computational design algorithm is molecule generation, where the machine is required to design high-quality, drug-like molecules, within the appropriate chemical ... Read more >>

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[2020, :]

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Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy.

Haixia Sun, Daoyuan Chen, Siyue Zhan, Weijian Wu, Huiying Xu, Chunxiang Luo, Hui Su, Yanqiao Feng, Weiyan Shao, Arabella Wan, Binhua Zhou, Guohui Wan, Xianzhang Bu,

Blockade of immune checkpoint PD-1/PD-L1 facilitates the rescue of immune escapes of tumor cells. Though various monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenges of protein-protein interaction (PPI) blocker design. In this work, we adopted the ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Ultrapotent inhibitor of Clostridioides difficile growth, which suppresses recurrence in vivo.

George Naclerio, Nader S Abutaleb, Daoyi Li, Mohamed N Seleem, Herman O Sintim,

Clostridioides difficile (C. difficile) is the leading cause of healthcare-associated infection in the U.S. and considered an urgent threat by the Centers for Disease Control and Prevention (CDC). Only two antibiotics, vancomycin and fidaxomicin, are FDA-approved for the treatment of C. difficile infection (CDI) but these therapies still suffer from ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Discovery and Characterization of BAY 1214784, an Orally Available Spiroindoline Derivative Acting as a Potent and Selective Antagonist of the Human Gonadotropin-Releasing Hormone Receptor as Proven in a First-in-Human Study in Postmenopausal Women.

Olaf Panknin, Andrea Wagenfeld, Wilhelm Bone, Eckhard Bender, Katrin Nowak-Reppel, Amaury E Fernández-Montalván, Reinhard Nubbemeyer, Stefan Bäurle, Sven Ring, Norbert Schmees, Olaf Prien, Martina Schäfer, Christian Friedrich, Thomas M Zollner, Andreas Steinmeyer, Thomas Mueller, Gernot Langer,

The growth of uterine fibroids is sex hormone dependent and commonly associated with highly incapacitating symptoms. Most treatment options consist of the control of these hormonal effects, ultimately blocking proliferative estrogen signaling (i.e., oral contraceptives/antagonization of human Gonadotropin-Releasing Hormone Receptor [hGnRH-R] activity). Full hGnRH-R blockade, however, results in menopausal symptoms ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Screening and Reverse-Engineering of Estrogen Receptor Ligands as Potent Pan-Filovirus Inhibitors.

Laura Cooper, Adam Schafer, Yangfeng Li, Han Cheng, Bani Medegan Fagla, Zhengnan Shen, Raghad Nowar, Katherine Dye, Manu Anantpadma, Robert A Davey, Gregory R J Thatcher, Lijun Rong, Rui Xiong,

Filoviridae, including Ebola (EBOV) and Marburg (MARV) viruses, are emerging pathogens that pose a serious threat to public health. No agents have been approved to treat filovirus infections, representing a major unmet medical need. The selective estrogen receptor modulator (SERM) toremifene was previously identified from a screen of FDA-approved drugs ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Glucosylpolyphenols as inhibitors of Aβ-induced Fyn kinase activation and Tau phosphorylation: synthesis, membrane permeability, and exploratory target assessment within the scope of type 2 diabetes and Alzheimer's disease.

Ana Marta de Matos, M Teresa Blázquez-Sánchez, Andreia Bento-Oliveira, Rodrigo de Almeida, Rafael Santana Nunes, Pedro LOpes, Miguel Machuqueiro, Joana Cristovão, Cláudio M Gomes, Cleide S Souza, Imane G El Idrissi, Nicola Antonio Colabufo, Ana Diniz, Filipa Marcelo, M Conceição Oliveira, Óscar López, José G Fernández-Bolaños, Philipp Dätwyler, Beat Ernst, Ke Ning, Claire Garwood, Beining Chen, Amelia Pilar Rauter,

Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases and cholinesterases. Moreover, ... Read more >>

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[2020, :]

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Repurposing of Drugs-The Ketamine Story.

Joydip Das,

An intranasal formulation of esketamine, the S enantiomer of ketamine, in conjunction with an oral antidepressant, has been approved by the FDA for treating treatment-resistant major depressive disorder (TRD) in 2019, almost 50 years after it was approved as an intravenous anesthetic. In contrast to traditional antidepressants, ketamine shows a ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Discovery of Small-Molecule Inhibitors of Receptor Activator of Nuclear Factor-κB Ligand (RANKL) with Superior Therapeutic Index.

Vagelis Rinotas, Athanasios Papakyriakou, Foteini Violitzi, Christos Papaneophytou, Maria-Dimitra Ouzouni, Polyxeni Alexiou, Alexandros T Strongilos, Elias Andreas Couladouros, George A Kontopidis, Elias Eliopoulos, Eleni Douni,

Receptor activator of nuclear factor-κB ligand (RANKL) constitutes the master mediator of osteoclastogenesis, while its pharmaceutical inhibition by a monoclonal antibody has been approved for the treatment of postmenopausal osteoporosis. To date, the pursuit of pharmacologically more favorable approaches using low-molecular-weight inhibitors has been hampered by low specificity and high ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ).

Konstantin Hinnah, Sabine Willems, Johannes Morstein, Jan Heering, Felix W W Hartrampf, Johannes Broichhagen, Philipp Leippe, Daniel Merk, Dirk Trauner,

Photopharmacology aims at the optical control of protein activity using synthetic photoswitches. This approach has been recently expanded to nuclear hormone receptors with the introduction of "photohormones" for the retinoic acid receptor, farnesoid X receptor, and estrogen receptor. Herein, we report the development and profiling of photoswitchable agonists for peroxisome ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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Novel Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Favorable Druggability.

Tong Zhao, Qing Meng, Zhuosen Sun, Yanyu Chen, Wei Ai, Zean Zhao, Dongwei Kang, Yue Dong, Ruipeng Liang, Ting Wu, Jianxin Pang, Xinyong Liu, Peng Zhan,

Lesinurad, a human urate transporter 1 (URAT1) inhibitor approved as a medication for the treatment of hyperuricemia associated with gout in 2015, can cause liver and renal toxicity. Here, we modified all three structural components of lesinurad by applying scaffold hopping, bioisosterism, and substituent-decorating strategies. In a mouse model of ... Read more >>

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[2020, :]

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