journal
MENU ▼
Read by QxMD icon Read
search

Journal of Medicinal Chemistry

journal
https://www.readbyqxmd.com/read/29792714/docking-screens-for-dual-inhibitors-of-disparate-drug-targets-for-parkinson-s-disease
#1
Mariama Jaiteh, Alexey Zeifman, Marcus Saarinen, Per Svenningsson, José M Brea, Maria Isabel Loza, Jens Carlsson
Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson's disease. A library with 5.4 million molecules was docked to crystal structures of the A2A adenosine receptor (A2AAR) and monoamine oxidase B (MAO-B)...
May 24, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29792703/structure-based-design-of-inhibitors-with-improved-selectivity-for-steroidogenic-cytochrome-p450-17a1-over-cytochrome-p450-21a2
#2
Charlie Fehl, Caleb D Vogt, Rahul Yadav, Kelin Li, Emily E Scott, Jeffrey Aubé
Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site...
May 24, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29787262/discovery-of-novel-pazopanib-based-hdac-and-vegfr-dual-inhibitors-targeting-cancer-epigenetics-and-angiogenesis-simultaneously
#3
Jie Zang, Xuewu Liang, Yongxue Huang, Yuping Jia, Xiaoyang Li, Wenfang Xu, C James Chou, Yingjie Zhang
Herein a novel series of pazopanib hybrids as polypharmacological antitumor agents were developed based on the crosstalk between histone deacetylases (HDACs) and vascular endothelial growth factor (VEGF) pathway. Among them, one ortho-aminoanilide 6d and one hydroxamic acid 13f exhibited considerable total HDACs and VEGFR-2 inhibitory activities. The HDAC inhibitory activities endowed 6d and 13f with potent antiproliferative activities, which was not observed in the approved VEGFR inhibitor pazopanib. Compounds 6d and 13f possessed comparable HDAC isoform selectivity profiles to the clinical class I HDAC inhibitor MS-275 and the approved pan-HDAC inhibitor SAHA, respectively...
May 22, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29782167/potent-and-highly-selective-inhibitors-of-the-proteasome-trypsin-like-site-by-incorporation-of-basic-side-chain-containing-amino-acid-derived-sulfonyl-fluorides
#4
Raik Artschwager, David Ward, Susan Gannon, Arwin J Brouwer, Helmus van de Langemheen, Hubert Kowalski, Rob Liskamp
A unique category of basic side chain containing amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site of the 20S proteasome. Masking the former α-amino functionality of the amino acid starting derivatives as an azido functionality, allowed an elegant conversion to the corresponding amino acid derived sulfonyl fluorides. The inclusion of different SFs at the P1 site of a proteasome inhibitor resulted in 14 different peptido sulfonyl fluorides (PSFs) having a high potency and an excellent selectivity for the proteolytic activity of the β2 subunit over that of the β5 subunit...
May 21, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29782164/editorial-on-first-time-disclosures-of-clinical-candidates
#5
Bruce E Maryanoff
No abstract text is available yet for this article.
May 21, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29779382/specific-stereoisomeric-conformations-determine-the-drug-potency-of-cladosporin-scaffold-against-malarial-parasite
#6
Pronay Das, Palak Babbar, Nipun Malhotra, Manmohan Sharma, Gorakhnath R Jachak, Rajesh G Gonnade, Dhanasekaran Shanmugam, Karl Harlos, Manickam Yogavel, Amit Sharma, D Srinivasa Reddy
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332...
May 21, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775538/discovery-of-potent-and-centrally-active-6-substituted-5-fluoro-1-3-dihydro-oxazine-%C3%AE-secretase-bace1-inhibitors-via-active-conformation-stabilization
#7
Kenji Nakahara, Kouki Fuchino, Kazuo Komano, Naoya Asada, Genta Tadano, Tsuyoshi Hasegawa, Takahiko Yamamoto, Yusuke Sako, Masayoshi Ogawa, Chie Unemura, Motoko Hosono, Hisanori Ito, Gaku Sakaguchi, Shigeru Ando, Shuichi Ohnishi, Yasuto Kido, Tamio Fukushima, Deborah Dhuyvetter, Herman Borghys, Harrie J M Gijsen, Yoshinori Yamano, Yasuyoshi Iso, Ken-Ichi Kusakabe
β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analog of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775310/fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-which-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2
#8
Tom D Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko Maria Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E H Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M Griffiths-Jones, John F Lyons, Vanessa Martins, Sandra Muench, Joanne M Munck, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C Rees, Sharna J Rich, Caroline Richardson, Harpreet Saini, Neil T Thompson, Nicola G Wallis, Hugh Walton, Nicola E Wilsher, Alison J-A Woolford, Michael Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John Watts, Christopher W Murray
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775303/simultaneous-targeting-of-rgd-integrins-and-dual-murine-double-minute-proteins-in-glioblastoma-multiforme
#9
Francesco Merlino, Simona Daniele, Valeria La Pietra, Salvatore Di Maro, Francesco Saverio Di Leva, Diego Brancaccio, Stefano Tomassi, Stefano Giuntini, Linda Cerofolini, Marco Fragai, Claudio Luchinat, Florian Reichart, Chiara Cavallini, Barbara Costa, Rebecca Piccarducci, Sabrina Taliani, Federico Da Settimo, Claudia Martini, Horst Kessler, Ettore Novellino, Luciana Marinelli
In the fight against Glioblastoma Multiforme, recent literature data have highlighted that integrin α5β1 and p53 are part of convergent pathways in the control of glioma apoptosis. This observation prompted us to seek a molecule able to simultaneously modulate both target families. Analyzing the results of a previous virtual screening against murine double minute 2 protein (MDM2), we envisaged that Arg-Gly-Asp (RGD)-mimetic molecules could be inhibitors of MDM2/4. Herein we present the discovery of compound 7, which inhibits both MDM2/4 and α5β1/αvβ3 integrins...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775297/factor-xia-inhibitors-as-new-anticoagulants
#10
Mimi L Quan, Donald J P Pinto, Joanne M Smallheer, William R Ewing, Karen A Rossi, Joseph M Luettgen, Dietmar A Seiffert, Ruth R Wexler
With the introduction of thrombin and factor Xa inhibitors to the oral anticoagulant market, significant improvements in both efficacy and safety have been achieved. Early clinical and preclinical data suggest that inhibitors of factor XIa can provide a still safer alternative, with expanded efficacy for arterial indications. This Perspective provides an overview of target rationale and details of the discovery and development of inhibitors of factor XIa as next generation antithrombotic agents.
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775064/enhancing-action-of-positive-allosteric-modulators-through-the-design-of-dimeric-compounds
#11
Thomas Drapier, Pierre Geubelle, Charlotte Bouckaert, Lise Nielsen, Saara Laulumaa, Eric Goffin, Sébastien Dilly, Pierre Francotte, Julien Hanson, Lionel Pochet, Jette Sandholm Kastrup, Bernard Pirotte
The present study describes the identification of highly potent dimeric 1,2,4-benzothiadiazine 1,1-dioxide (BTD)-type positive allosteric modulators of the AMPA receptors (AMPApams) obtained by linking two monomeric BTD scaffolds through their respective 6-positions. Using previous X-ray data from monomeric BTDs co-crystallized with the GluA2o ligand-binding domain (LBD), a molecular modeling approach was performed to predict the preferred dimeric combinations. Two 6,6-ethylene-linked dimeric BTD compounds (16 and 22) were prepared and evaluated as AMPApams on HEK293 cells expressing GluA2o(Q) (calcium flux experiment)...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29772905/retraction-of-development-of-a-novel-class-of-glucose-transporter-inhibitors
#12
Dasheng Wang, Po-Chen Chu, Chia-Ning Yang, Ribai Yan, Yu-Chung Chuang, Samuel K Kulp, Ching-Shih Chen
No abstract text is available yet for this article.
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29772897/retraction-of-development-of-novel-adenosine-monophosphate-activated-protein-kinase-activators
#13
Jih-Hwa Guh, Wei-Ling Chang, Jian Yang, Su-Lin Lee, Shuo Wei, Dasheng Wang, Samuel K Kulp, Ching-Shih Chen
No abstract text is available yet for this article.
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29772180/determination-of-affinity-and-residence-time-of-potent-drug-target-complexes-by-label-free-biosensing
#14
John G Quinn, Keith E Pitts, Micah Steffek, Mela M Mulvihill
Prolonged drug-target occupancy has become increasingly important in lead optimization, and biophysical assays that measure residence time are in high demand. Here we report a practical label-free assay methodology that provides kinetic and affinity measurements suitable for most target classes without long pre-incubations and over comparatively short sample contact times. The method, referred to as a "chaser" assay, has been applied to three sets of unrelated kinase/inhibitor panels in order to measure the residence times, where correlation with observed efficacy was suspected...
May 17, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29771541/plasmodial-kinase-inhibitors-license-to-cure
#15
Diego Gonzalez Cabrera, André Horatscheck, Colin Rylott Wilson, Gregory S Basarab, Charles J Eyermann, Kelly Chibale
Advances in the genetics, function and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compound libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity...
May 17, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29771525/an-nmr-biochemical-assay-for-oxidosqualene-cyclase-evaluation-of-inhibitor-activities-on-trypanosoma-cruzi-and-human-enzymes
#16
Osamu Tani, Yukie Akutsu, Shinji Ito, Takayuki Suzuki, Yukihiro Tateishi, Tomohiko Yamaguchi, Tatsuya Niimi, Ichiji Namatame, Yasunori Chiba, Hitoshi Sakashita, Tomomi Kubota, Tetsuo Yanagi, Shusaku Mizukami, Kenji Hirayama, Koji Furukawa, Kazuhiko Yamasaki
Oxidosqualene cyclase (OSC), a membrane-associated protein, is a key enzyme of sterol biosynthesis. Here we report a novel assay for OSC, involving reaction in aqueous solution, NMR quantification in organic solvent, and factor analysis of spectra. We evaluated one known and three novel inhibitors on OSC of Trypanosoma cruzi, a parasite causative of Chagas disease, and compared with their effects on human OSC for selectivity. Among them, one novel inhibitor showed a significant parasiticidal activity.
May 17, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29771523/phosphorus-based-probes-as-molecular-tools-for-proteome-studies-recent-advances-in-probe-development-and-applications
#17
Łukasz Joachimiak, Katarzyna M Blazewska
Studies on the human proteome have engaged diverse techniques; however, none of them represent a predominant approach. Chemical biology has made a major contribution to our understanding of human biology, stimulating the generation of biological hypotheses. Tools such as functional probes have advanced studies on biological mechanisms and helped in elucidating off-target reactivity and potential toxicities of drugs and drug candidates. Here, we accentuate the recent developments in the design and applications of phosph(on)ate-containing probes...
May 17, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29768008/striking-a-balance-between-carbonate-carbamate-linkage-bond-and-reduction-sensitive-disulfide-bond-bearing-linker-for-tailored-controlled-release-in-situ-covalently-albumin-binding-gemcitabine-prodrugs-promote-bioavailability-and-tumor-accumulation
#18
Huicong Zhang, Kuanglei Wang, Kexin Na, Dan Li, Zhenbao Li, Dongyang Zhao, Lu Zhong, Menglin Wang, Longfa Kou, Cong Luo, Haotian Zhang, Qiming Kan, Huaiwei Ding, Zhonggui He, Jin Sun
To address the challenge of rapid enzyme inactivation, poor tumor targeting, acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalised GEM prodrugs conjugating covalently in situ with cys-34 of blood-circulating albumin, resulting in macromolecular prodrugs after intravenous administration. Specially, tailored and accurate controlled release was achieved through different combinations of linkage bonds relatively stable and labile (carbamate and carbonate, respectively) and linkers with or without insertion of a disulfide bond...
May 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29767995/structure-activity-relationships-and-therapeutic-potentials-of-5-ht7-receptor-ligands-an-update
#19
Maria N Modica, Enza Lacivita, Sebastiano Intagliata, Loredana Salerno, Giuseppe Romeo, Valeria Pittala, Marcello Leopoldo
Serotonin 5-HT7 receptor (5-HT7R) has been the subject of intense research efforts because of its presence in brain areas such as hippocampus, hypothalamus, and cortex. Preclinical data link the 5-HT7R to a variety of central nervous system processes such as regulation of circadian rhythms, mood, cognitions, pain processing, and mechanisms of addiction. 5-HT7R blockade has antidepressant effects and may ameliorate cognitive deficits associated with schizophrenia. 5-HT7R has been recently shown to modulate neuronal morphology, excitability, and plasticity, thus contributing to shape brain networks during development and to remodel neuronal wiring in the mature brain...
May 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29767974/in-vitro-and-in-vivo-demonstration-of-human-ovarian-cancer-necrosis-through-a-water-soluble-and-near-infrared-absorbing-chlorin
#20
Betsy Marydasan, Bollapalli Madhuri, Shirisha Cherukommu, Jedy Jose, Mambattakkara Viji, Suneesh C Karunakaran, Tavarekere K Chandrashekar, Kunchala Sridhar Rao, Ch Mohan Rao, Danaboyina Ramaiah
With an objective to develop efficient sensitizers for therapeutical applications, we synthesized a water soluble, 5,10,15,20-tetrakis(3,4-dihydroxyphenyl)chlorin (TDC), and investigated its in vitro and in vivo biological efficacy and compared with the commercially available sensitizers. TDC showed high water solubility (6-fold), when compared to Foscan and exhibited excellent triplet excited state () and singlet oxygen () yields. In vitro photobiological investigations in human ovarian cancer cell lines SKOV-3 showed high photocytotoxicity, negligible dark toxicity, rapid cellular uptake and specific localization of TDC in neoplastic cells as assessed by flow cytometric cell-cycle and propidium iodide staining analysis...
May 16, 2018: Journal of Medicinal Chemistry
journal
journal
32885
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"