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Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/28745898/development-of-a-mitochondriotropic-antioxidant-based-on-caffeic-acid-proof-of-concept-on-cellular-and-mitochondrial-oxidative-stress-models
#1
José Teixeira, Fernando Cagide, Sofia Benfeito, Pedro Soares, Jorge Garrido, Inês Baldeiras, José A Ribeiro, Carlos M Pereira, António F Silva, Paula B Andrade, Paulo J Oliveira, Fernanda M Borges
Targeting mitochondrial oxidative stress is an effective therapeutic strategy. In this context, a rational design of mitochondriotropic antioxidants (compounds 22 to 27) based on a dietary antioxidant (caffeic acid) was performed. Jointly named as AntiOxCINs, these molecules take advantage of the known ability of the triphenylphosphonium cation to target active molecules to mitochondria. The study was guided by structure-activity-toxicity-property relationships and we demonstrate in this work that the novel AntiOxCINs act as mitochondriotropic antioxidants...
July 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28745893/microbiota-host-transgenomic-metabolism-bioactive-molecules-from-the-inside
#2
Silvia Turroni, Patrizia Brigidi, Andrea Cavalli, Marco Candela
Molecular factors from the gut microbiota provide the host with the right metabolic, immunological and neurological components to support health and wellbeing. However, certain circumstances can rupture the mutualistic pact with our intestinal counterpart, pushing the gut microbiome toward a dysbiotic layout, where microbiome-derived molecules may contribute to a disease state. We are now beginning to understand the microbiota-host co-regulated pathways underlying these processes, paving the way for a new era of rational piloting of the gut microbiome functions, through the design of a new generation of microbiome-targeting drugs...
July 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28745887/phthalazino-1-2-b-quinazolinones-as-p53-activators-cell-cycle-arrest-apoptotic-response-and-bak-bcl-xl-complex-reorganization-in-bladder-cancer-cells
#3
Guo-Hai Zhang, Jing-Mei Yuan, Gang Qian, Chen-Xi Gu, Kai Wei, Dong-Liang Mo, Jiang-Ke Qin, Yan Peng, Zuping Zhou, Cheng-Xue Pan, Gui-Fa Su
p53 inactivation is a clinically defined characteristic for cancer treatment-nonresponsiveness. It is therefore highly desirable to develop anticancer agents by restoring p53 function.1 Herein the synthesized phthalazino[1,2-b]- -quinazolinones were discovered as p53 activators in bladder cancer cells. 10-Bromo-5-(2-dimethylamino-ethylamino)phthalazino[1,2-b]quinazolin-8-one (5da) was identified as the most promising candidate in view of both its anticancer activity and mechanisms of action. 5da exhibited strong anticancer activity on a broad range of cancer cell lines and significantly reduced tumor growth in xenograft models at doses as low as 6 mg/kg...
July 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28745507/discovery-of-potent-orally-active-protease-activated-receptor-1-par1-antagonists-based-on-andrographolide
#4
Jun Liu, Bin Sun, Xiaoyu Zhao, Jie Xing, Yanhui Gao, Wenqiang Chang, Jianbo Ji, Hongbo Zheng, Changyi Cui, Aiguo Ji, Hong-Xiang Lou
Protease-activated receptor-1 (PAR1), a G protein-coupled receptor, plays a critical role in thrombin-mediated platelet aggregation. It is regarded as a promising antithrombosis target that is unlikely to result in bleeding. Here, we describe the synthesis of a series of novel PAR1 antagonists by borrowing the chiral fragment of andrographolide, an easily accessible natural molecule from Andrographis paniculata, to produce natural product/synthesis hybrids. An in vitro PAR1 inhibition assay and an in vivo pharmacokinetic profile led to the identification of compound 39 as the best PAR1 inhibitor...
July 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28745501/free-energy-methods-in-drug-design-the-prospects-of-alchemical-perturbation-in-medicinal-chemistry
#5
Billy J Williams-Noonan, Elizabeth Yuriev, David K Chalmers
Underpinning all drug discovery projects is the interaction between a drug and its target, usually a protein. Thus, improved methods for predicting the magnitude of protein-ligand interactions have the potential to improve the efficiency of drug development. In this review, we describe the principles of free energy methods used for the calculation of protein-ligand binding free energies, the challenges associated with these methods, and recent advances developed to address these difficulties. We then present case studies from 2005-2017, each demonstrating that alchemical free energy methods can assist rational drug design projects...
July 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28598634/design-and-synthesis-of-%C3%AE-and-%C3%AE-lactam-m1-positive-allosteric-modulators-pams-convulsion-and-cholinergic-toxicity-of-an-m1-selective-pam-with-weak-agonist-activity
#6
Jennifer E Davoren, Michelle Garnsey, Betty Pettersen, Michael A Brodney, Jeremy R Edgerton, Jean-Philippe Fortin, Sarah Grimwood, Anthony R Harris, Stephen Jenkinson, Terry Kenakin, John T Lazzaro, Che-Wah Lee, Susan M Lotarski, Lisa Nottebaum, Steven V O'Neil, Michael Popiolek, Simeon Ramsey, Stefanus J Steyn, Catherine A Thorn, Lei Zhang, Damien Webb
Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects...
July 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28741954/side-chain-modified-ergosterol-and-stigmasterol-derivatives-as-liver-x-receptor-agonists
#7
Maura Marinozzi, Francisco Fermin Castro Navas, Daniela Maggioni, Emanuele Carosati, Giovanni Bocci, Maria Carloncelli, Gianluca Giorgi, Gabriele Cruciani, Raffaella Fontana, Vincenzo Russo
A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRβ isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRβ, while it was virtually inactive at LXRα (EC50 = 14...
July 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28686445/discovery-and-optimization-of-chromeno-2-3-c-pyrrol-9-2h-ones-as-novel-selective-and-orally-bioavailable-phosphodiesterase-5-inhibitors-for-the-treatment-of-pulmonary-arterial-hypertension
#8
Deyan Wu, Tianhua Zhang, Yiping Chen, Yadan Huang, Haiju Geng, Yanfa Yu, Chen Zhang, Zengwei Lai, Yinuo Wu, Xiaolei Guo, Jianwen Chen, Hai-Bin Luo
Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63...
July 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28665128/discovery-of-the-irreversible-covalent-fgfr-inhibitor-8-3-4-acryloylpiperazin-1-yl-propyl-6-2-6-dichloro-3-5-dimethoxyphenyl-2-methylamino-pyrido-2-3-d-pyrimidin-7-8h-one-prn1371-for-the-treatment-of-solid-tumors
#9
Ken A Brameld, Timothy D Owens, Erik Verner, Eleni Venetsanakos, J Michael Bradshaw, Vernon T Phan, Danny Tam, Kwan Leung, Jin Shu, Jacob LaStant, David G Loughhead, Tony Ton, Dane E Karr, Mary E Gerritsen, David M Goldstein, Jens Oliver Funk
Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition...
July 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28737946/structure-guided-optimization-of-hiv-integrase-strand-transfer-inhibitors
#10
Xue Zhi Zhao, Steven J Smith, Daniel P Maskell, Mathieu Métifiot, Valerie E Pye, Katherine Fesen, Christophe Marchand, Yves Pommier, Peter Cherepanov, Stephen H Hughes, Terrence R Burke
Integrase mutations can reduce effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG) has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates...
July 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28737935/the-current-state-of-peptide-drug-discovery-back-to-the-future
#11
Antoine Henninot, James C Collins, John M Nuss
Over the last decade, peptide drug discovery has experienced a revival of interest and scientific momentum, as the pharmaceutical industry has come to appreciate the role that peptide therapeutics can play in addressing unmet medical needs, and how this class of compounds can be an excellent complement or even preferable alternative to small molecule and biological therapeutics. In this perspective we give a concise description of the recent progress in peptide drug discovery in a holistic manner, highlighting enabling technological advances affecting nearly every aspect of this field: from lead discovery, to synthesis and optimization, to peptide drug delivery...
July 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28737909/inhibitory-kappa-b-kinse-%C3%AE-ikk%C3%AE-inhibitors-that-recapitulate-their-selectivity-in-cells-against-isoform-related-biomarkers
#12
Nahoum G Anthony, Jessica Baiget, Giacomo Berretta, Marie Boyd, David Breen, Joanne Edwards, Carly Gamble, Alexander I Gray, Alan L Harvey, Sophia Hatziieremia, Ka Ho Ho, Judith K Huggan, Stuart Lang, Sabin Llona-Minguez, Jia Lin Luo, Kathryn McIntosh, Andrew Paul, Robin J Plevin, Murray N Robertson, Rebecca Scott, Colin J Suckling, Oliver Brook Sutcliffe, Louise C Young, Simon Paul Mackay
IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterised. The role of IKKα in the non-canonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ, until now. Herein, we report for the first time a series of novel, potent and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the non-canonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway...
July 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28699738/a-molecular-combination-of-zinc-ii-phthalocyanine-and-tamoxifen-derivative-for-dual-targeting-photodynamic-therapy-and-hormone-therapy
#13
Feng-Ling Zhang, Mei-Ru Song, Gan-Kun Yuan, Huan-Nian Ye, Ye Tian, Ming-Dong Huang, Jin-Ping Xue, Zhi-Hong Zhang, Jian-Yong Liu
The combination of photodynamic therapy and other cancer treatment modalities is a promising strategy to enhance therapeutic efficacy and reduce side effects. In this study, a tamoxifen-zinc(II) phthalocyanine conjugate linked by a triethylene glycol chain has been synthesized and characterized. Having tamoxifen as the targeting moiety, the conjugate shows high specific affinity to MCF-7 breast cancer cells overexpressed estrogen receptors (ERs) and tumor tissues, therefore leading to a cytotoxic effect in the dark due to the cytostatic tamoxifen moiety, and a high photocytotoxicity due to the photosensitizing phthalocyanine unit against the MCF-7 cancer cells...
July 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28731719/discovery-structure-activity-relationship-and-binding-mode-of-imidazo-1-2-a-pyridine-series-of-autotaxin-inhibitors
#14
Agnès Joncour, Nicolas Desroy, Christopher Housseman, Xavier Bock, Natacha Bienvenu, Laëtitia Cherel, Virginie Labeguere, Christophe Peixoto, Denis Annoot, Luce Lepissier, Jörg Heiermann, Willem Jan Hengeveld, Gregor Pilzak, Alain Monjardet, Emanuelle Wakselman, Veronique Roncoroni, Sandrine Le Tallec, René Galien, Christelle David, Nele Vandervoort, Thierry Christophe, Katja Conrath, Mia Jans, Alexandre Wohlkonig, Robert Touitou, Damien Fleury, Lionel Vercheval, Patrick Mollat, Nicolas Triballeau, Ellen Van der Aar, Reginald Brys, Bertrand Heckmann
Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases and inflammation among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high throughput screening (HTS). A co-crystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site...
July 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28731336/triple-reuptake-inhibitors-as-potential-therapeutics-for-depression-and-other-disorders-design-paradigm-and-developmental-challenges
#15
Murugaiah A M Subbaiah
Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability...
July 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28731335/a-simple-representation-of-three-dimensional-molecular-structure
#16
Seth D Axen, Xi-Ping Huang, Elena L Cáceres, Leo Gendelev, Bryan L Roth, Michael J Keiser
Statistical and machine learning approaches predict drug-to-target relationships from 2D small-molecule topology patterns. One might expect 3D information to improve these calculations. Here we apply the logic of the Extended Connectivity FingerPrint (ECFP) to develop a rapid, alignment-invariant 3D representation of molecular conformers, the Extended Three-Dimensional FingerPrint (E3FP). By integrating E3FP with the Similarity Ensemble Approach (SEA), we achieve higher precision-recall performance relative to SEA with ECFP on ChEMBL20, and equivalent receiver operating characteristic performance...
July 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28657745/recent-advances-in-structure-based-drug-design-targeting-class-a-g-protein-coupled-receptors-utilizing-crystal-structures-and-computational-simulations
#17
Yoonji Lee, Shaherin Basith, Sun Choi
G protein-coupled receptors (GPCRs) represent the largest and most physiologically important integral membrane protein family, and these receptors respond to a wide variety of physiological and environmental stimuli. GPCRs are among the most critical therapeutic targets for numerous human diseases, and approximately one-third of the currently marketed drugs target this receptor family. The recent breakthroughs in GPCR structural biology have significantly contributed to our understanding of GPCR function, ligand binding, and pharmacological action as well as to the design of new drugs...
July 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28726402/opioid-receptor-modulators-with-a-cinnamyl-group
#18
Lokesh Ravilla, N Venkata Subba Naidu, Shalini Dogra, Deepmala Umrao, Prem N Yadav, Ansuman Biswas, Daliah Michael, Kanagaraj Sekar, Kuppuswamy Nagarajan
To obtain selective and potent opioid receptor ligands, we synthesized dehydro derivatives of alvimopan and found compound (28f), a selective but modest affinity MOR antagonist, weaker than alvimopan (1). We replaced the aryl piperidine unit by an aryl piperazine to obtain the 1-(α-carboxycinnamyl)-4-arylpiperazines like (13h), which to our surprise had no MOR or DOR activity but was a KOR agonist with moderate affinity. In contrast, literature examples of aryl piperazines (4) and (5) were reported to be pan opioid receptor antagonists, while (6) was a MOR agonist...
July 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28726401/amidoalkylindoles-as-potent-and-selective-cannabinoid-type-2-receptor-agonists-with-in-vivo-efficacy-in-a-mouse-model-of-multiple-sclerosis
#19
Ying Shi, Yan-Hui Duan, Yue-Yang Ji, Zhi-Long Wang, Yan-Ran Wu, Hendra Gunosewoyo, Xiao-Yu Xie, Jian-Zhong Chen, Fan Yang, Jing Li, Jie Tang, Xin Xie, Li-Fang Yu
Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor...
July 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28682609/conformation-based-design-and-synthesis-of-apratoxin-a-mimetics-modified-at-the-%C3%AE-%C3%AE-unsaturated-thiazoline-moiety
#20
Yuichi Onda, Yuichi Masuda, Masahito Yoshida, Takayuki Doi
We have demonstrated design, synthesis, and biological evaluation of apratoxin A mimetics. In the first generation, the moCys moiety was replaced with seven simple amino acids as their 3D structures can be similar to that of apratoxin A. Apratoxins M1-M7 were synthesized using solid-phase peptide synthesis and solution-phase macrolactamization. Apratoxin M7, which contains a piperidinecarboxylic acid moiety, exhibited potent cytotoxicity against HCT-116 cells. In the second generation, substitution of each amino acid residue in the tripeptide Tyr(Me)-MeAla-MeIle moiety in apratoxin M7 led to the development of the highly potent apratoxin M16 possessing biphenylalanine (Bph) instead of Tyr(Me), which exhibited an IC50 value of 1...
July 20, 2017: Journal of Medicinal Chemistry
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