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Journal of Medicinal Chemistry

Brian Provencher, Amy J Eshleman, Robert A Johnson, Xiao Shi, Olga Kryatova, Jared Nelson, Jianhua Tian, Mario Gonzalez, Peter C Meltzer, Aaron Janowsky
Methamphetamine, a human vesicular monoamine transporter 2 (VMAT2) substrate, releases dopamine, serotonin and norepinephrine from vesicles into the cytosol of presynaptic neurons and induces reverse transport by the monoamine transporters to increase extracellular neurotransmitters. Currently available radioligands for VMAT2 have considerable liabilities: The binding of [3H]dihydrotetrabenazine ([3H]DHTB) to a site on VMAT2 is not dependent on ATP and thus less closely associated with VMAT2 function, and [3H]reserpine binds almost irreversibly to VMAT2...
September 21, 2018: Journal of Medicinal Chemistry
Yingpeng Liu, Lipin Ji, Marsha Eno, Shalley Kudalkar, Ai-Ling Li, Marion Schimpgen, Othman Benchama, Paula Morales, Shu Xu, Dow Hurst, Simiao Wu, Khadijah A Mohammad, JodiAnne T Wood, Nikolai Zvonok, Demetris P Papahatjis, Han Zhou, Chandrashekhar Honrao, Ken Mackie, Patricia Reggio, Andrea G Hohmann, Lawrence J Marnett, Alexandros Makriyannis, Spyros P Nikas
The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13 S,1' R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor ( Ki of 7.8 ± 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC50 = 0.6 ± 0.2 nM). (13 S,1' R)-dimethylanandamide is the first potent AEA analogue with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model, 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analogue AM356...
September 21, 2018: Journal of Medicinal Chemistry
Rafał Kurczab, Vittorio Canale, Grzegorz Satała, Paweł Zajdel, Andrzej J Bojarski
A computational approach combining a structure-activity relationship library of halogenated and the corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was used to search for amino acids frequently targeted by halogen bonding (hot spots) in a 5-HT7 R as a case study. The procedure identified two sets of hot spots, extracellular (D2.65, T2.64, and E7.35) and transmembrane (C3.36, T5.39, and S5.42), which were further verified by a synthesized library of halogenated arylsulfonamide derivatives of (aryloxy)ethylpiperidines...
September 21, 2018: Journal of Medicinal Chemistry
Radek Jorda, Denisa Hendrychová, Jiří Voller, Eva Řezníčková, Tomas Gucky, Vladimir Krystof
Cyclin-dependent kinases (CDKs) are an important and emerging class of drug targets, for which many small-molecule inhibitors have been developed. However, there is often insufficient data available on the selectivity of CDK inhibitors (CDKi) to attribute the effects on the presumed target CDK to these inhibitors. Here, we highlight discrepancies between the kinase selectivity of CDKi and the phenotype exhibited; we evaluated 31 CDKi (claimed to target CDK1-4) for activity towards CDKs 1/2/4/5/7/9 and for effects on the cell cycle...
September 20, 2018: Journal of Medicinal Chemistry
Fabian Hulpia, Kristof Van Hecke, Cristiane França da Silva, Denise da Gama Jaén Batista, Louis Maes, Guy Caljon, Maria de Nazaré Correia Soeiro, Serge Van Calenbergh
Chagas disease is the leading cause of cardiac-related mortality in endemic Latin American countries. Trypanosoma cruzi, the disease-causing pathogen, is unable to synthesize purines de novo, necessitating salvage of pre-formed host purine building blocks. Therefore, modified purine and purine nucleoside analogs might constitute an attractive source to identify antitrypanosomal hits. In this study, structural elements of two purine nucleoside analogs, i.e. cordycepin and a recently discovered 7-substituted 7-deazaadenosine led to the identification of novel nucleoside analogs with potent in vitro activity against T...
September 20, 2018: Journal of Medicinal Chemistry
Panfeng Peng, Huan Chen, Ya Zhu, Zhi-Long Wang, Jian Li, Ronghua Luo, Jiang Wang, Liang Chen, Liu-Meng Yang, Hualiang Jiang, Xin Xie, Beili Wu, Yong-Tang Zheng, Hong Liu
CC-chemokine receptor 5 (CCR5) is an attractive target to prevent the entry of HIV-1 into human host cells. Maraviroc is the only one CCR5 antagonist marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition, and to enhance anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1-34) were synthesized, displaying CCR5 antagonist activities in the 2.3-296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity and low cytotoxicity, an acceptable pharmacokinetic profile...
September 20, 2018: Journal of Medicinal Chemistry
Sébastien L Degorce, Michael S Bodnarchuk, Iain A Cumming, James S Scott
In this article, we report our investigation of a phenomenon by which bridging morpholines across the ring with one-carbon tethers leads to a counterintuitive reduction in lipophilicity. This effect was also found to occur in piperazines and piperidines and lowered the measured log D7.4 of the bridged molecules by as much as -0.8 relative to their unbridged counterparts. As lowering lipophilicity without introducing additional heteroatoms can be desirable, we believe this potentially provides a useful tactic to improve the drug-like properties of molecules containing morpholine-, piperazine-, and piperidine-like motifs...
September 20, 2018: Journal of Medicinal Chemistry
Martina Tassinari, Graziella Cimino-Reale, Matteo Nadai, Filippo Doria, Elena Butovskaya, Marta Recagni, Mauro Freccero, Nadia Zaffaroni, Sara N Richter, Marco Folini
Stabilization of the G-quadruplexes (G4s) within the androgen receptor (AR) gene promoter to block transcription may represent an innovative approach to interfere with aberrant AR signaling in castration resistant prostate cancer (CRPC). A library of differently functionalized naphthalene diimides (NDIs) was screened for their ability to stabilize AR G4s: the core-extended NDI (7) stood out as the most promising ligand. AR-positive cells were remarkably sensitive to 7 in comparison to AR-negative CRCP or normal prostate epithelial cells; 7 induced remarkable impairment of AR mRNA and protein amounts and significant perturbations in the expression levels of KLK3 and of genes involved in the activation of AR program via feedback mechanisms...
September 20, 2018: Journal of Medicinal Chemistry
James P C Coverdale, Hannah E Bridgewater, Ji-Inn Song, Nichola A Smith, Nicolas P E Barry, Ian Bagley, Peter J Sadler, Isolda Romero Canelon
Platinum drugs are widely used for cancer treatment. Other precious metals are promising, but their clinical progress depends on achieving different mechanisms of action to overcome Pt-resistance. Here we evaluate 13 organo-Os complexes: 16-electron sulfonyl-diamine catalysts [(η6-arene)Os(N,N')] and 18-electron phenylazopyridine complexes [(η6-arene)Os(N,N')Cl/I]+ (arene = p-cymene, biphenyl or terphenyl). Their antiproliferative activity does not depend on p21 or p53 status, unlike cisplatin, and their selective potency towards cancer cells involves the generation of reactive oxygen species...
September 19, 2018: Journal of Medicinal Chemistry
Chao Wang, Lei Zhao, Shuai Xia, Tianhong Zhang, Ruiyuan Cao, Guodong Liang, Yue Li, Guangpeng Meng, Weicong Wang, Weiguo Shi, Wu Zhong, Shibo Jiang, Keliang Liu
Class I enveloped viruses share similarities in their apparent use of a hexameric coiled-coil assembly to drive the merging of virus and host cell membranes. Inhibition of coiled coil-mediated interactions using bioactive peptides that replicate an α-helical chain from the viral fusion machinery has significant antiviral potential. Here, we present the construction of a series of lipopeptides composed of a de novo heptad repeat sequence-based α-helical peptide plus a hydrocarbon tail. Promisingly, the constructs adopted stable α-helical conformations and exhibited relatively broad-spectrum antiviral activities against Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza A viruses (IAVs)...
September 19, 2018: Journal of Medicinal Chemistry
Wei Yan, Naga Rajiv Lakkaniga, Francesca Carlomagno, Massimo Santoro, Neil Q McDonald, Fengping Lv, Naresh Gunaganti, Brendan Frett, Hong-Yu Li
The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors...
September 19, 2018: Journal of Medicinal Chemistry
Etienne Billard, Terence E Hébert, David Chatenet
Urotensin II (UII) and urotensin II-related peptide (URP) are functionally selective, suggesting that these two hormones might play distinct physiological role through different interactions with their cognate receptor UT. Hypothesizing that the Phe3 residue of URP, which is also present in UII, is a key-element of its specific UT activation, we evaluated the impact of its replacement by non-natural amino acids in URP. Each compound was evaluated for its ability to bind UT, induce rat aortic ring contraction, and activate Gq , G12 , and β-arrestin 1 signaling pathways...
September 19, 2018: Journal of Medicinal Chemistry
Hayley Whitfield, Megan Gilmartin, Kendall Baker, Andrew M Riley, H Y Godage, Barry V L Potter, Andrew M Hemmings, Charles A Brearley
Inositol pentakisphosphate 2-kinase catalyzes the phosphorylation of the axial 2-OH of myo-inositol 1,3,4,5,6-pentakisphosphate for de novo synthesis of myo-inositol hexakisphosphate. Disruption of inositol pentakisphosphate 2-kinase profoundly influences cellular processes, from nuclear mRNA export and phosphate homeostasis in yeast and plants to establishment of left-right asymmetry in zebrafish. We elaborate an active site fluorescent probe that allows high throughput screening of Arabidopsis inositol pentakisphosphate 2-kinase...
September 19, 2018: Journal of Medicinal Chemistry
Peichen Pan, Jiean Chen, Xijian Li, Miyang Li, Huidong Yu, Jean J Zhao, Jing Ni, Xuwen Wang, Huiyong Sun, Sheng Tian, Feng Zhu, Feng Liu, Yong Huang, Tingjun Hou
Camptothecin (CPT) has been demonstrated to block disassembly of topoisomerase-I (Topo I)/DNA cleavable complex. The poor aqueous solubility, intrinsic instability and severe toxicity of CPTs provide extensive playing fields to develop improved drugs. Herein, we report the design and synthesis of water-soluble and oral bioavailable hexacyclic CPT derivatives. By virtual combinatorial library analysis, compounds 9 and 11 emerged as leads that demonstrate remarkable in vivo efficacy in both tumor and sepsis models, and improved drug-like profiles...
September 18, 2018: Journal of Medicinal Chemistry
Patrick S Lee, Guillaume Lapointe, Ann Marie Madera, Robert Simmons, Wenjian Xu, Aregahegn Yifru, Meiliana Tjandra, Subramanian Karur, Alice Rico, Katherine Thompson, Jade Bojkovic, Lili Xie, Kyoko Uehara, Amy Liu, Wei Shu, Cornelia Bellamacina, David McKenney, Laura Morris, Colin S Osborne, Bret Benton, Laura McDowell, Jiping Fu, Zachary K Sweeney
This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models...
September 18, 2018: Journal of Medicinal Chemistry
Paul Bamborough, Chun-Wa Chung, Rebecca C Furze, Paola Grandi, Anne-Marie Michon, Robert J Watson, Darren J Mitchell, Heather Barnett, Rab K Prinjha, Christina Rau, Robert J Sheppard, Thilo Werner, Emmanuel H Demont
ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected...
September 18, 2018: Journal of Medicinal Chemistry
Antonio Laghezza, Luca Piemontese, Carmen Cerchia, Roberta Montanari, Davide Capelli, Marco Giudici, Maurizio Crestani, Paolo Tortorella, Franck Peiretti, Giorgio Pochetti, Antonio Lavecchia, Fulvio Loiodice
A new series of derivatives of the PPARα/γ dual agonist 1 allowed us to identify the ligand ( S)-6 as a potent partial agonist of both PPARα and γ subtypes. X-ray studies in PPARγ revealed two different binding modes of ( S)-6 to the canonical site. However, ( S)-6 was also able to bind an alternative site as demonstrated by transactivation assay in the presence of a canonical PPARγ antagonist and supported from docking experiments. This compound did not activate the PPARγ-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone but increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes...
September 18, 2018: Journal of Medicinal Chemistry
Mingcheng Qian, Elise Wouters, James A R Dalton, Martijn D P Risseeuw, René A J Crans, Christophe Stove, Jesús Giraldo, Kathleen Van Craenenbroeck, Serge Van Calenbergh
In this study, we designed and synthesized heterobivalent ligands targeting heteromers consisting of the metabotropic glutamate 5 receptor (mGluR5) and the dopamine D2 receptor (D2 R). Bivalent ligand 22a with a linker consisting of 20 atoms showed 4-fold increase in affinity for cells coexpressing D2 R and mGluR5 compared to cells solely expressing D2 R. Likewise, the affinity of 22a for mGluR5 increased 2-fold in the coexpressing cells. Additionally, 22a exhibited a 5-fold higher mGluR5 affinity than its monovalent precursor 21a in cells coexpressing D2 R and mGluR5...
September 18, 2018: Journal of Medicinal Chemistry
Brandt C Huddle, Edward Grimley, Cameron D Buchman, Mikhail Chtcherbinine, Bikash Debnath, Pooja Mehta, Kun Yang, Cynthia A Morgan, Siwei Li, Jeremy Antonio Felton, Duxin Sun, Geeta Metha, Nouri Neamati, Ronald J Buckanovich, Thomas D Hurley, Scott D Larsen
Aldehyde dehydrogenase (ALDH) activity is commonly used as a marker to identify cancer stem-like cells. The three ALDH1A isoforms have all been individually implicated in cancer stem-like cells and in chemoresistance; however, which isoform is preferentially expressed varies between cell lines. We sought to explore the structural determinants of ALDH1A isoform selectivity in a series of small molecule inhibitors in support of research into the role of ALDH1A in cancer stem cells. An SAR campaign guided by a co-crystal structure of the HTS hit CM39 (7) with ALDH1A1 afforded first-in-class inhibitors of the ALDH1A subfamily with excellent selectivity over the homologous ALDH2 isoform...
September 17, 2018: Journal of Medicinal Chemistry
Maxime Gicquel, Catherine Gomez, Maria Concepcion Garcia Alvarez, Olivier Pamlard, Vincent Guérineau, Eric Jacquet, Jérôme Bignon, Arnaud Voituriez, Angela Marinetti
3,3'-spirocyclopentene oxindoles structurally related to the Wang's spiropyrrolidine oxindoles, have been highlighted as a new class of antiproliferative agents against cancer cell lines with wild-type p53 Status (IC50 up to 0.96 M on SJSA-1 and 2.9 M in HCT116 p53-wt). Inhibition of the MDM2-p53 interactions has been demonstrated through in vitro HTRF assays (IC50 up to 3.1 nM), while Western blot analysis showed activation of p53 selectively in HCT116 cancer cell lines with wild type p53.
September 17, 2018: Journal of Medicinal Chemistry
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