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Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/29148769/azetidine-and-piperidine-carbamates-as-efficient-covalent-inhibitors-of-monoacylglycerol-lipase
#1
Christopher R Butler, Elizabeth M Beck, Anthony R Harris, Zhen Huang, Laura A McAllister, Christopher W Am Ende, Kimberly F Fennell, Timothy L Foley, Kari R Fonseca, Steven J Hawrylik, Douglas S Johnson, John D Knafels, Scot Mente, Stephen Noell, Jayvardhan Pandit, Tracy B Phillips, Justin R Piro, Bruce N Rogers, Tarek A Samad, Jane Wang, Shuangyi Wan, Michael A Brodney
Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the pro-inflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL was aided by the generation of inhibitor-bound MAGL crystal structures...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29148763/discovery-of-n-3-carbamoyl-5-5-7-7-tetramethyl-5-7-dihydro-4h-thieno-2-3-c-pyran-2-yl-lh-pyrazole-5-carboxamide-glpg1837-a-novel-potentiator-which-can-open-class-iii-mutant-cystic-fibrosis-transmembrane-conductance-regulator-cftr-channels-to-a-high-extent
#2
Steven Emiel Van der Plas, Hans Kelgtermans, Tom De Munck, Sébastien Laurent Xavier Martina, Sébastien Dropsit, Evelyne Quinton, Ann De Blieck, Caroline Joannesse, Linda Tomaskovic, Mia Jans, Thierry Christophe, Ellen Van der Aar, Monica Borgonovi, Luc Nelles, Maarten Gees, Pieter Fw Stouten, Jan Van Der Schueren, Oscar Mammoliti, Katja Conrath, Martin J Andrews
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837 which shows enhanced efficacy on CFTR mutants harboring Class III mutations compared to Ivacaftor, the first marketed potentiator...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29148755/novel-anti-tubercular-6-dialkylaminopyrimidine-carboxamides-from-phenotypic-whole-cell-high-throughput-screening-of-a-softfocus-library-structure-activity-relationship-and-target-identification-studies
#3
Colin R Wilson, Richard K Gessner, Atica Moosa, Ronnett Seldon, Digby F Warner, Valerie Mizrahi, Candice Soares de Melo, Sandile B Simelane, Aloysius T Nchinda, Efrem Abay, Dale Taylor, Mathew Njoroge, Christel Brunschwig, Nina Lawrence, Helena I M Boshoff, Clifton E Barry, Frederick A Sirgel, Paul van Helden, C John Harris, Richard Gordon, Sonja Ghidelli-Disse, Hannah Pflaumer, Markus Boesche, Gerard Drewes, Olalla Sanz, Gracia Santos, Maria José Rebollo-Lopez, Beatriz Urones, Carolyn Selenski, Maria Jose Lafuente-Monasterio, Matthew Axtman, Joël Lelièvre, Lluis Ballell, Rudolf Mueller, Leslie J Street, Sandeep R Ghorpade, Kelly Chibale
A BioFocus DPI SoftFocus library of ~35,000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with anti-tubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1 complex, disruption of cell-wall homeostasis, and DNA damage. Among the hits which passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29116785/a-positive-allosteric-modulator-of-the-serotonin-5-ht2c-receptor-for-obesity
#4
Javier García-Cárceles, Juan M Decara, Henar Vázquez-Villa, Ramón Rodríguez, Eva Codesido, Jacobo Cruces, José Brea, María I Loza, Francisco Alén, Joaquin Botta, Peter J McCormick, Juan A Ballesteros, Bellinda Benhamú, Fernando Rodríguez de Fonseca, María L López-Rodríguez
The 5-HT2CR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HT2CR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogues 6-41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29112446/relevance-of-half-life-in-drug-design
#5
Dennis A Smith, Kevin Beaumont, Tristan S Maurer, Li Di
Drug half-life has important implications for dosing regimen and peak-to-trough ratio at the steady state. A half-life of 12-48 h is generally ideal for once daily dosing of oral drugs. If the half-life is too short, it may require more frequent dosing in order to maintain desired exposures and avoid unnecessarily high peak concentrations. This may pose challenges to achieving optimal efficacy, safety, and patient compliance. If the half-life is too long, the time over which accumulation and subsequent elimination occur may be prolonged...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29077405/discovery-of-a-parenteral-small-molecule-coagulation-factor-xia-inhibitor-clinical-candidate-bms-962212
#6
Donald J P Pinto, Michael J Orwat, Leon M Smith, Mimi L Quan, Patrick Y S Lam, Karen A Rossi, Atsu Apedo, Jeffrey M Bozarth, Yiming Wu, Joanna J Zheng, Baomin Xin, Nathalie Toussaint, Paul Stetsko, Olafur Gudmundsson, Brad Maxwell, Earl J Crain, Pancras C Wong, Zhen Lou, Timothy W Harper, Silvi A Chacko, Joseph E Myers, Steven Sheriff, Huiping Zhang, Xiaoping Hou, Arvind Mathur, Dietmar A Seiffert, Ruth R Wexler, Joseph M Luettgen, William R Ewing
Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29148806/discovery-of-tropifexor-ljn452-a-highly-potent-non-bile-acid-fxr-agonist-for-the-treatment-of-cholestatic-liver-diseases-and-nonalcoholic-steatohepatitis-nash
#7
David C Tully, Paul V Rucker, Donatella Chianelli, Jennifer Williams, Agnes Vidal, Phil B Alper, Daniel Mutnick, Badry Bursulaya, James Schmeits, Xiangdong Wu, Dingjiu Bao, Jocelyn Zoll, Young Kim, Todd Groessl, Peter McNamara, H Martin Seidel, Valentina Molteni, Bo Liu, Andrew Phimister, Sean B Joseph, Bryan Laffitte
The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and non-alcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold...
November 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29144748/chemical-modification-for-proteolytic-stabilization-of-the-selective-%C3%AE-v%C3%AE-3-integrin-rgdechi-peptide-in-vitro-and-in-vivo-activities-on-malignant-melanoma-cells
#8
Daniela Comegna, Antonella Zannetti, Annarita Del Gatto, Ivan de Paola, Luigi Russo, Sonia Di Gaetano, Annamaria Liguoro, Domenica Capasso, Michele Saviano, Laura Zaccaro
Herein we report the synthesis and biological characterization of the novel peptide ψRGDechi as the first step towards novel targeted theranostics in melanoma. This pseudo-peptide is designed from our previously reported RGDechi peptide, known to bind selectively αvβ3 integrin, and differs for a modified amide bond at the main protease cleavage site. This chemical modification drastically reduces the enzymatic degradation in serum, compared to its parental peptide, resulting in an overall magnification of the biological activity on a highly expressing αvβ3 human metastatic melanoma cell line...
November 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29144739/protac-induced-protein-degradation-in-drug-discovery-breaking-the-rules-or-just-making-new-ones
#9
Ian Churcher
Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degradation concepts, and their resulting applications to medicine discovery...
November 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29144137/design-of-novel-3-pyrimidinylazaindole-based-cdk2-9-inhibitors-with-potent-in-vitro-and-in-vivo-antitumor-efficacy-in-a-triple-negative-breast-cancer-model
#10
Umed Singh, Gousia Chashoo, Sameer U Khan, Priya Mahajan, Amit Nargotra, Girish Mahajan, Amarinder Singh, Anjna Sharma, Mubashir Javeed Mintoo, Santosh Kumar Guru, Hariprasad Aruri, Thanusha Thatikonda, Promod Sahu, Pankaj Chibber, Vikas Kumar, Sameer A Mir, Sonali S Bharate, Sreedhar Madishetti, Utpal Nandi, Gurdarshan Singh, Dilip Manikrao Mondhe, Shashi Bhushan, Fayaz Malik, Serge Mignani, Ram A Vishwakarma, Parvinder Pal Singh
In the present study, novel series of 3-pyrimidinylazaindoles were designed and synthesized using bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in cell-cycle control and regulation of cell transcription. The present approach has given new dimensions to existing SAR and opens the new opportunity for lead optimization from comparatively inexpensive starting materials. The study led to the identification of alternative lead candidate 4ab with nanomolar potency against CDK2 and CDK9 and potent anti-proliferative activities against a panel of tested tumor cell lines along better safety ratio of ~30 in comparison to reported leads...
November 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29140695/rna-g-quadruplexes-in-kirsten-ras-kras-oncogene-as-targets-for-small-molecules-inhibiting-translation
#11
Giulia Miglietta, Susanna Cogoi, Jessica Marinello, Giovanni Capranico, Alexander S Tikhomirov, Andrey E Shchekotikhin, Luigi E Xodo
The human KRAS transcript contains a G-rich 5'-UTR sequence (77 % GC) harbouring several G4 motifs capable to form stable RNA G-quadruplex (RG4) structures that can serve as targets for small molecules. A biotin-streptavidin pull-down assay showed that 4,11-bis(2-aminoethylamino)anthra[2,3-b]furan-5,10-dione (2a) binds to RG4s in the KRAS transcript under low-abundance cellular conditions. Dual-luciferase assays demonstrated that 2a and its analogue 4,11-bis(2-aminoethylamino)anthra[2,3-b]thiophene-5,10-dione 2b) repress translation in a dose-dependent manner...
November 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29140694/tyrocidine-a-analogues-bearing-the-planar-d-phe-2-abz-turn-motif-how-conformation-impacts-bioactivity
#12
Alan J Cameron, Patrick J B Edwards, Elena Harjes, Vijayalekshmi Sarojini
The D-Phe-Pro β-turn of the cyclic β-hairpin antimicrobial decapeptide Tyrocidine A, (Tyrc A) was substituted with the D-Phe-2-aminobenzoic acid (2-Abz) motif in a synthetic analogue (1). NMR structure of 1 demonstrated that compound 1 retained the β-hairpin structure of Tyrc A with additional planarity, resulting in approx. 30-fold reduced haemolysis than Tyrc A. Although antibacterial activity was partially compromised, a single Gln to Lys substitution (2) restored activity equivalent to Tyrc A against S...
November 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29140691/on-the-importance-of-rigidity-in-designing-small-molecule-drugs-to-tackle-protein-protein-interactions-ppis-through-stabilisation-of-desired-confomers
#13
Alastair D G Lawson, Malcolm MacCoss, Jag P Heer
Tackling PPIs, particularly by stabilising clinically favoured conformations of target proteins, with orally available, bona fide small molecules remains a significant, but immensely worthwhile, challenge for the pharmaceutical industry. Success may be more likely through the application of nature's learnings to build intrinsic rigidity into the design of clinical candidates.
November 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29136469/novel-linear-lipopeptide-paenipeptins-with-potential-for-eradicating-biofilms-and-sensitizing-gram-negative-bacteria-to-rifampicin-and-clarithromycin
#14
Sun Hee Moon, Xuan Zhang, Guangrong Zheng, Daniel G Meeker, Mark S Smeltzer, En Huang
We report the structure-activity relationship (SAR) analyses of 17 linear lipopeptide paenipeptin analogues. Analogues 7, 12 and 17 were more potent than the lead compound. Analogue 17 was active against carbapenem-resistant and polymyxin-resistant pathogens. This compound at 40 μg/mL resulted in 3 log and 2.6 log reductions of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, respectively, in catheter-associated biofilms in vitro. Analogue 17 showed little hemolysis at 32 µg/ml and lysed 11% of red blood cells at 64 µg/ml...
November 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29136465/recent-progress-of-small-molecule-epidermal-growth-factor-receptor-egfr-inhibitors-against-c797s-resistance-in-non-small-cell-lung-cancer
#15
Lingfeng Chen, Weitao Fu, Lulu Zheng, Zhiguo Liu, Guang Liang
The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein797 to serine790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs...
November 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29135250/structure-activity-relationships-of-6-and-8-gingerol-analogs-as-anti-biofilm-agents
#16
Hyunsuk Choi, So-Young Ham, Eunji Cha, Yujin Shin, Han-Shin Kim, Jeong Kyu Bang, Sang-Hyun Son, Hee-Deung Park, Youngjoo Byun
Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in P. aeruginosa. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation...
November 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29111705/one-bead-two-compound-thioether-bridged-macrocyclic-%C3%AE-aapeptide-screening-library-against-epha2
#17
Yan Shi, Sridevi Challa, Peng Sang, Fengyu She, Chunpu Li, Geoffrey M Gray, Alekhya Nimmagadda, Peng Teng, Timothy Odom, Yan Wang, Arjan van der Vaart, Qi Li, Jianfeng Cai
Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two-compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics γ-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected α-amino acids, which were orthogonal to solid phase synthesis of γ-AApeptides...
November 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29045781/development-of-clickable-monophosphoryl-lipid-a-derivatives-toward-semisynthetic-conjugates-with-tumor-associated-carbohydrate-antigens
#18
Marcello Ziaco, Sabina Górska, Serena Traboni, Agnieszka Razim, Angela Casillo, Alfonso Iadonisi, Andrzej Gamian, Maria Michela Corsaro, Emiliano Bedini
A semisynthetic strategy to obtain monophosphoryl lipid A derivatives equipped with clickable (azide, alkyne, double bond, or thiol precursor) moieties, starting from the native lipid A isolated from Escherichia coli, is presented. These lipid A derivatives can be conjugated with other interesting biomolecules, such as tumor-associated carbohydrate antigens (TACAs). In this way, the immunostimulant activity of monophosphoryl lipid A can significantly improve the immunogenicity of TACAs, thus opening access to potential self-adjuvant anticancer vaccine candidates...
November 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29131958/design-synthesis-and-biological-assessment-of-biased-allosteric-modulation-of-the-urotensin-ii-receptor-using-achiral-1-3-4-benzotriazepin-2-one-turn-mimics
#19
Antoine Douchez, Étienne Billard, Terence Hébert, David Chatenet, William D Lubell
Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip(4)]URP), which modulates the urotensin II receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex-vivo rat aortic ring bioassay...
November 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29094944/design-of-mc1r-selective-%C3%AE-msh-analogues-with-canonical-amino-acids-leads-to-potency-and-pigmentation
#20
Yang Zhou, Saghar Mowlazadeh Haghighi, Ioanna Zoi, Jonathon R Sawyer, Victor J Hruby, Minying Cai
Melanoma is a lethal form of skin cancer. Skin pigmentation, which is regulated by the melanocortin 1 receptor (MC1R), is an effective protection against melanoma. However, the endogenous MC1R agonists lack selectivity for the MC1R and thus can have side effects. The use of noncanonical amino acids in previous MC1R ligand development raises safety concerns. Here we report the development of the first potent and selective hMC1R agonist with only canonical amino acids. Using γ-MSH as a template, we developed a peptide, [Leu(3), Leu(7), Phe(8)]-γ-MSH-NH2 (compound 5), which is 16-fold selective for the hMC1R (EC50 = 4...
November 13, 2017: Journal of Medicinal Chemistry
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