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ACS Medicinal Chemistry Letters

Kuldip D Upadhyay, Narsinh M Dodia, Rupesh C Khunt, Ravi S Chaniara, Anamik K Shah
A series of pyrano[3,2- c ]quinoline based structural analogues was synthesized using one-pot multicomponent condensation between 2,4-dihydroxy-1-methylquinoline, malononitrile, and diverse un(substituted) aromatic aldehydes. The synthesized compounds were evaluated for their anti-inflammatory and cytotoxicity activity. Initially, all the compounds were evaluated for the percent inhibition of cytokine release, and cytotoxicity activity and 50% inhibitory concentrations (IC50 ) were also determined. Based on the primary results, it was further studied for their ability to inhibit TNF-α production in the human peripheral blood mononuclear cells (hPBMC) assay...
March 8, 2018: ACS Medicinal Chemistry Letters
Zackary M Herbst, Sayaka Shibata, Erkang Fan, Michael H Gelb
An inexpensive, in-house made microdialysis device is described that is suitable for measuring the binding of small molecules including drug candidates to serum proteins or other macromolecules. The device is based on the standard equilibrium dialysis method to measure the fraction of low molecular weight compound bound to proteins. It is constructed from a standard polypropylene 96-well plate, dialysis tubing, and low viscosity epoxy resin. The device can be readily prepared for a small fraction of the cost of a commercial, multichamber microdialysis device...
March 8, 2018: ACS Medicinal Chemistry Letters
Xiaofan Liu, Yanping Wang, Richard I Duclos, George A O'Doherty
Tetrahydrolipstatin (THL), its enantiomer, and an additional six diastereomers were evaluated as inhibitors of the hydrolysis of p -nitrophenyl butyrate by porcine pancreatic lipase. IC50 s were found for all eight stereoisomers ranging from a low of 4.0 nM for THL to a high of 930 nM for the diastereomer with the inverted stereocenters at the 2,3,2'-positions. While the enantiomer of THL was also significantly less active (77 nM) the remaining five stereoisomers retained significant inhibitory activities (IC50 s = 8...
March 8, 2018: ACS Medicinal Chemistry Letters
Li Huang, Wei-Hong Lai, Lei Zhu, Wei Li, Lei Wei, Kuo-Hsiung Lee, Lan Xie, Chin-Ho Chen
We have previously reported gnidimacrin (GM), a protein kinase C (PKC) agonist, significantly reduces the frequency of HIV-1 latently infected cells in peripheral blood mononuclear cells (PBMCs) from patients undergoing successful antiretroviral therapy at low picomolar concentrations ex vivo , which is distinct from other latency reversing agents. In this study, we demonstrate that strong viral reactivation by GM is a mechanism for elimination of latently infected cells, and a histone deacetylase inhibitor (HDACI), a thiophenyl benzamide (TPB), further potentiated the efficacy of GM against latent HIV-1...
March 8, 2018: ACS Medicinal Chemistry Letters
Qiuping Xiang, Yan Zhang, Jiaguo Li, Xiaoqian Xue, Chao Wang, Ming Song, Cheng Zhang, Rui Wang, Chenchang Li, Chun Wu, Yulai Zhou, Xiaohong Yang, Guohui Li, Ke Ding, Yong Xu
Prostate cancer is a commonly diagnosed cancer and a leading cause of cancer-related deaths. The bromodomain and extra terminal domain (BET) family proteins have emerged as potential therapeutic targets for the treatment of castration-resistant prostate cancer. A series of 2,2-dimethyl-2 H -benzo[ b ][1,4]oxazin-3(4 H )-one derivatives were designed and synthesized as selective bromodomain containing protein 4 (BRD4) inhibitors. The compounds potently inhibit BRD4(1) with nanomolar IC50 values and exhibit high selectivity over most non-BET subfamily members...
March 8, 2018: ACS Medicinal Chemistry Letters
Tao Yu, Ning Li, Chengde Wu, Amy Guan, Yi Li, Zhengang Peng, Miao He, Jie Li, Zhen Gong, Lei Huang, Bo Gao, Dongling Hao, Jikui Sun, Yan Pan, Liang Shen, Chichung Chan, Xiulian Lu, Hongyu Yuan, Yongguo Li, Jian Li, Shuhui Chen
The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31 . Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cell assays, and good pharmacokinetic profile. Furthermore, compound 31 demonstrated in vivo efficacy in a PC-3M tumor xenograft model.
March 8, 2018: ACS Medicinal Chemistry Letters
Francisco Lopez-Tapia, Christine Brotherton-Pleiss, Peibin Yue, Heide Murakami, Ana Carolina Costa Araujo, Bruna Reis Dos Santos, Erin Ichinotsubo, Anna Rabkin, Raj Shah, Megan Lantz, Suzie Chen, Marcus A Tius, James Turkson
The molecular determinants for the activities of the reported benzoic acid (SH4-54), salicylic acid (BP-1-102), and benzohydroxamic acid (SH5-07)-based STAT3 inhibitors were investigated to design optimized analogues. All three leads are based on an N -methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. The three functionalities and the CH2 group of the glycinamide scaffold were separately modified. The replacement of the pentafluorobenzene or cyclohexylbenzene, or replacing the benzene ring of the aromatic carboxylic or hydroxamic acid motif with heterocyclic components (containing nitrogen and oxygen elements) all decreased potency...
March 8, 2018: ACS Medicinal Chemistry Letters
Yuan Zhang, Vijai Kumar Reddy Tangadanchu, Yu Cheng, Ren-Guo Yang, Jian-Mei Lin, Cheng-He Zhou
A series of isopropanol-bridged carbazole azoles as potential antimicrobial agents were designed and synthesized from commercial carbazoles. Bioassay revealed that 3,6-dichlorocarbazolyl triazole 3f could effectively inhibit the growth of E. faecalis with minimal inhibitory concentration of 2 μg/mL. The active molecule 3f showed lower propensity to trigger the development of resistance in bacteria than norfloxacin and exerted rapidly bactericidal ability. Compound 3f also exhibited low cytotoxicity to normal mammalian RAW264...
March 8, 2018: ACS Medicinal Chemistry Letters
Colin R O'Dowd, Matthew D Helm, J S Shane Rountree, Jakub T Flasz, Elias Arkoudis, Hugues Miel, Peter R Hewitt, Linda Jordan, Oliver Barker, Caroline Hughes, Ewelina Rozycka, Eamon Cassidy, Keeva McClelland, Ewa Odrzywol, Natalie Page, Stephanie Feutren-Burton, Scarlett Dvorkin, Gerald Gavory, Timothy Harrison
Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography...
March 8, 2018: ACS Medicinal Chemistry Letters
Shuaishuai Ni, Baoli Li, Feifei Chen, Hanwen Wei, Fei Mao, Yifu Liu, Yixiang Xu, Xiaoxi Qiu, Xiaokang Li, Wenwen Liu, Linghao Hu, Dazheng Ling, Manjiong Wang, Xinyu Zheng, Jin Zhu, Lefu Lan, Jian Li
Diapophytoene desaturase (CrtN) is a potential novel target for intervening in the biosynthesis of the virulence factor staphyloxanthin. In this study, 38 1,4-benzodioxan-derived CrtN inhibitors were designed and synthesized to overwhelm the defects of leading compound 4a . Derivative 47 displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro. Notably, 47 displayed excellent efficacy against pigmented S...
March 8, 2018: ACS Medicinal Chemistry Letters
Marc Sousbie, Élie Besserer-Offroy, Rebecca L Brouillette, Jean-Michel Longpré, Richard Leduc, Philippe Sarret, Éric Marsault
Neurotensin exerts potent analgesic effects following activation of its cognate GPCRs. In this study, we describe a systematic exploration, using structure-based design, of conformationally constraining neurotensin (8-13) with the help of macrocyclization and the resulting impacts on binding affinity, signaling, and proteolytic stability. This exploratory study led to a macrocyclic scaffold with submicromolar binding affinity, agonist activity, and greatly improved plasma stability.
March 8, 2018: ACS Medicinal Chemistry Letters
Andreas Kling, Katja Jantos, Helmut Mack, Wilfried Hornberger, Gisela Backfisch, Yanbin Lao, Marjoleen Nijsen, Beatrice Rendenbach-Mueller, Achim Moeller
Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). 2-(3-Phenyl-1 H )-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays...
March 8, 2018: ACS Medicinal Chemistry Letters
Thomas Knoepfel, Pascal Furet, Robert Mah, Nicole Buschmann, Catherine Leblanc, Sebastien Ripoche, Diana Graus-Porta, Markus Wartmann, Inga Galuba, Robin A Fairhurst
As part of a project to identify FGFR4 selective inhibitors, scaffold morphing of a 2-formylquinoline amide hit identified series of 2-formylpyridine ureas (2-FPUs) with improved potency and physicochemical properties. In particular, tetrahydronaphthyridine urea analogues with cellular activities below 30 nM have been identified. Consistent with the hypothesized reversible-covalent mechanism of inhibition, the 2-FPUs exhibited slow binding kinetics, and the aldehyde, as the putative electrophile, could be demonstrated to be a key structural element for activity...
March 8, 2018: ACS Medicinal Chemistry Letters
Sreedhar R Tummalapalli, Rohit Bhat, Agnieszka Chojnowski, Monika Prorok, Tamara Kreiss, Ronald Goldberg, Stacie Canan, Natalie Hawryluk, Deborah Mortensen, Vikram Khetani, Jerome Zeldis, John J Siekierka, David P Rotella
Lymphatic filariasis infects over 120 million people worldwide and can lead to significant disfigurement and disease. Resistance is emerging with current treatments, and these therapies have dose limiting adverse events; consequently new targets are needed. One approach to achieve this goal is inhibition of parasitic protein kinases involved in circumventing host defense mechanisms. This report describes structure-activity relationships leading to the identification of a potent, orally bioavailable stress activated protein kinase inhibitor that may be used to investigate this hypothesis...
March 8, 2018: ACS Medicinal Chemistry Letters
Dominique Douguet
Presented here are several data sets that gather information collected from the labels of the FDA approved drugs: their molecular structures and those of the described active metabolites, their associated pharmacokinetics and pharmacodynamics data, and the history of their marketing authorization by the FDA. To date, 1852 chemical structures have been identified with a molecular weight less than 2000 of which 492 are or have active metabolites. To promote the sharing of data, the original web server was upgraded for browsing the database and downloading the data sets (http://chemoinfo...
March 8, 2018: ACS Medicinal Chemistry Letters
Antonios Drakopoulos, Christina Tzitzoglaki, Kelly McGuire, Anja Hoffmann, Athina Konstantinidi, Dimitrios Kolokouris, Chunlong Ma, Kathrin Freudenberger, Johanna Hutterer, Günter Gauglitz, Jun Wang, Michaela Schmidtke, David D Busath, Antonios Kolocouris
Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher k off rates compared to the k on rates according to electrophysiology (EP) measurements...
March 8, 2018: ACS Medicinal Chemistry Letters
Monica Sanna, Giovanna Sicilia, Ali Alazzo, Nishant Singh, Francesca Musumeci, Silvia Schenone, Keith A Spriggs, Jonathan C Burley, Martin C Garnett, Vincenzo Taresco, Cameron Alexander
A miniaturized assay was optimized to evaluate the enhanced apparent water solubility of pyrazolo[3,4- d ]pyrimidine derivatives used extensively as anticancer drug scaffolds. The applied amount of drugs used in the reported strategy ranged from 5 to 10 μg per formulation which were dispensed by an inkjet 2D printer directly into a 96-well plate. The selected polymer/drug formulations with high water solubility demonstrated improved cytotoxicity against a human lung adenocarcinoma cancer cell line (A549) compared to the free drugs...
March 8, 2018: ACS Medicinal Chemistry Letters
Fanxing Zeng, Jonathon A Nye, Ronald J Voll, Leonard Howell, Mark M Goodman
Nine pyridyloxypyridyl indole carboxamides were synthesized and displayed high affinities for 5-HT2C receptors and high selectivity over 5-HT2A and 5-HT2B . Among them, 6-methyl- N -[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]1 H -indole-3-carboxamide ( 8 ) exhibits the highest 5-HT2C binding affinity ( K i = 1.3 nM) and high selectivity over 5-HT2A (∼1000 times) and 5-HT2B (∼140 times). [11 C] 8 was synthesized by palladium-catalyzed coupling reaction between pinacolboranate 16 and [11 C]CH3 I with an average radiochemical yield of 27 ± 4% ( n = 8, decay-corrected from end of [11 C]CH3 I synthesis)...
March 8, 2018: ACS Medicinal Chemistry Letters
Kosuke Dodo, Tadashi Shimizu, Jun Sasamori, Kazuyuki Aihara, Naoki Terayama, Shuhei Nakao, Katsuya Iuchi, Masahiro Takahashi, Mikiko Sodeoka
We previously developed IM-54 as a novel type of inhibitor of hydrogen-peroxide-induced necrotic cell death. Here, we examined its cell death inhibition profile. IM-54 was found to selectively inhibit oxidative stress-induced necrosis, but it did not inhibit apoptosis induced by various anticancer drugs or Fas ligand, or necroptosis. IM-17 , an IM derivative having improved water-solubility and metabolic stability, was developed and confirmed to retain necrosis-inhibitory activity. IM-17 showed cardioprotective effects in an isolated rat heart model and an in vivo arrhythmia model, suggesting that IM derivatives may have therapeutic potential...
March 8, 2018: ACS Medicinal Chemistry Letters
Neydher Berroterán-Infante, Theresa Balber, Petra Fürlinger, Michael Bergmann, Rupert Lanzenberger, Marcus Hacker, Markus Mitterhauser, Wolfgang Wadsak
The overexpression of the translocator protein (TSPO) has been amply reported for a variety of conditions, including neurodegenerative disorders, heart failure, and cancer. Thus, TSPO has been proposed as an excellent imaging biomarker, allowing, in this manner, to obtain an accurate diagnosis and to follow disease progression and therapy response. Accordingly, several radioligands have been developed to accomplish this purpose. In this work, we selected [18 F]FEPPA, as one of the clinical established tracers, and assessed its in vitro performance in colorectal cancer...
March 8, 2018: ACS Medicinal Chemistry Letters
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