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PubMed Journal Database | Journal of medicinal chemistry RSS

05:57 EDT 26th April 2017 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage PubMed.gov which comprises of more than 21 million records, papers, reports for biomedical literature, including MEDLINE, life science and medical journals, articles, reviews, reports and  books.  BioPortfolio aims to publish relevant information on published papers, clinical trials and news associated with users selected topics.

For example view all recent relevant publications on Epigenetics and associated publications and clincial trials.

Showing PubMed Articles 1–25 of 2,700+ from Journal of medicinal chemistry

Discovery of a Novel Class of Survival Motor Neuron 2 Splicing Modifiers for the Treatment of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene, resulting in low levels of functional SMN protein. We have reported recently the identification of small molecules (coumarins, iso-coumarins and pyrido-pyrimidinones) that modify the alternative splicing of SMN2, a paralogous gene to SMN1, restoring the survival motor neuron (SMN) protein level in mouse models of SMA. Herein, we report our efforts to identify a novel chemotype as one strategy to poten...

A naturally occurring isoform-specific probe for highly selective and sensitive detection of human cytochrome P450 3A5.

Cytochrome P450 (CYP) 3A5 characterized with polymorphic and extensive expression in multiple tissues is the most important P450 enzyme among the minor CYP3A isoforms. However, a selective and sensitive probe for CYP3A5 remains unavailable. In this study, we identified and characterized a naturally-occurring lignan 12 (Schisantherin E) as an isoform-specific probe for selective detection of CYP3A5 activity in complex biological samples. With thorough characterization including LC-MS and NMR, we found that 1...

Allosteric targeting of the Fanconi anemia ubiquitin-conjugating enzyme Ube2T by fragment screening.

Ube2T is the E2 ubiquitin-conjugating enzyme of the Fanconi anemia DNA repair pathway and it's overexpressed in several cancers, representing an attractive target for the development of inhibitors. Despite the extensive efforts in targeting the ubiquitin system, very few E2 binders have currently been discovered. Herein we report the identification of a new allosteric pocket on Ube2T through a fragment screening using biophysical methods. Several fragments binding to this site inhibit ubiquitin conjugation ...

Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity.

Estrogen receptor (ER) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesised - series I containing an acrylic acid, series II with an acrylamide and series III with an acid substuent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a p...

Development of a 18F-labeled radiotracer with improved brain kinetics for positron emission tomography imaging of translocator protein (18 kDa) in ischemic brain and glioma.

We designed four novel acetamidobenzoxazolone compounds 7a-d as candidates of positron emission tomography (PET) radiotracers for imaging translocator protein (18 kDa, TSPO) in ischemic brain and glioma. Among these compounds, 2-(5-(6-fluoropyridin-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-methyl-N-phenylacetamide (7d) exhibited high binding affinity (Ki = 13.4 nM) with TSPO and moderate lipophilicity (LogD: 1.92). [18F]7d was radiosynthesized by [18F]fluorination of the bromopyridine precursor 7h with [18F]F- ...

Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.

Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compounds had decreased permeability, low human nNOS activity, and low selectivity versus human eNOS. In this study, 5-substituted phenyl ether-lin...

Discovery of 2-2-Ethyl-6-4-2-(3-hydroxyazetidin-1-yl)-2-oxo-ethylpiperazin-1-yl-8-methyl-imidazo1,2-apyridin-3-yl-methyl-amino-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis.

Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained ...

Topical intestinal aminoimidazole agonists of G-Protein-Coupled Bile Acid Receptor 1 promote Glucagon Like Peptide-1 secretion and improve glucose tolerance.

The role of the G-Protein-coupled Bile Acid Receptor TGR5 in various organs, tissues and cell types, specifically in intestinal endocrine L-cells and brown adipose tissue, has made it a promising therapeutical target in several diseases, especially type-2 diabetes and metabolic syndrome. However, recent studies have shown deleterious on-target effects of systemic TGR5 agonists. To avoid these systemic effects while stimulating Glucagon Like Peptide-1 (GLP-1) secreting enteroendocrine L-cells, we have design...

Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/ mTOR Dual Inhibitors.

Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. A series of dimorpholine substituted thienopyrimidine derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor, which had an approximately 8-fold improvement in mTOR inhibition relative to the class I PI3K inhibitor 1 (pictilisib, GDC-0941)....

Amphiphilic tobramycin-lysine conjugates sensitize multidrug resistant Gram-negative bacteria to rifampicin and minocycline.

Chromosomally-encoded low membrane permeability and highly efficient efflux systems are major mechanisms by which Pseudomonas aeruginosa evades antibiotic actions. Our previous reports have shown that amphiphilic tobramycin-fluoroquinolone hybrids can enhance efficacy of fluoroquinolone antibiotics against multidrug-resistant (MDR) P. aeruginosa isolates. Herein, we report on a novel class of tobramycin-lysine conjugates containing an optimized amphiphilic tobramycin-C12 tether which sensitize Gram-negative...

1-(4-(18)FFluorobenzyl)-4-((tetrahydrofuran-2-yl)methyl)piperazine: A novel suitable radioligand with low lipophilicity for imaging sigma-1 receptors in the brain.

We have designed and synthesized novel piperazine compounds with low lipophilicity as σ1 receptor ligands. 1-(4-Fluorobenzyl)-4-((tetrahydrofuran-2-yl)methyl)piperazine (10) possessed low nanomolar σ1 receptor affinity and high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ2 receptors (52-fold), adenosine A2A, adrenergic α2, cannabinoid CB1, dopamine D1, D2L, γ-aminobutyric acid A (GABAA), NMDA, melatonin MT1, MT2 and serotonin 5-HT1 receptors. The corresponding radiotracer ...

Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease.

Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of Inflammatory Bowel Disease (IBD). In this work, we report the design, the synthesis, and the biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a non-toxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β release from ma...

Reversing the Cytotoxicity of Bile Acids by Supramolecular Encapsulation.

Supramolecular encapsulation has been developed into a powerful tool in clearance of toxic substances and hazardous waste from living body and external environments. Herein we tested the special efficacy of tyramine-modified β-cyclodextrin (1) in inhibiting and reversing the inherent cytotoxicity of deoxycholic acid (DCA). The decarboxylation from tyrosine to tyramine in 1 is crucial to the mutual electrostatic communication, ultimately leading to great enhancement in binding affinity and molecular selecti...

Inhibitors of 15-Prostaglandin Dehydrogenase to Potentiate Tissue Repair.

The enzyme 15-prostaglandin dehydrogenase (15-PGDH) catalyzes the first step in the degradation of prostaglandins including PGE2. It is a negative regulator of tissue repair and regeneration in multiple organs. Accordingly, inhibitors of 15-PGDH are anticipated to elevate in vivo levels of PGE2 and to promote healing and tissue regeneration. The small molecule SW033291 (1) inhibits 15-PGDH with Ki = 0.1 nM in vitro, doubles PGE2 levels in vivo, and shows efficacy in mouse models of recovery from bone marrow...

DETERMINATION OF IN VITRO AND IN SILICO INDEXES FOR THE MODELLING OF BLOOD-BRAIN BARRIER PARTITIONING OF DRUGS VIA MICELLAR AND IMMOBILIZED ARTIFICIAL MEMBRANE LIQUID CHROMATOGRAPHY.

In the present work, 79 structurally unrelated analytes were taken into account and their chromatographic retention coefficients, measured by Immobilized Artificial Membrane Liquid Chromatography (IAM-LC), and by Micellar Liquid Chromatography (MLC) employing sodium dodecyl sulfate (SDS) as surfactant, were determined. Such indexes were subsequently used for the development of Blood-Brain Barrier passage-predictive statistical models using partial least square (PLS) regression along with topological and phy...

A tobramycin vector enhances synergy and efficacy of efflux pump inhibitors against multidrug-resistant Gram-negative bacteria.

Drug efflux mechanisms interact synergistically with the outer membrane permeability barrier of Gram-negative bacteria leading to intrinsic resistance that presents a major challenge for antibiotic drug development. Efflux pump inhibitors (EPIs) which block the efflux of antibiotics synergize antibiotics but the clinical development of EPI/antibiotic combination therapy to treat multidrug-resistant (MDR) Gram-negative infections has been challenging. This is in part caused by the inefficiency of current EPI...

Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases.

The design of selective matrix metalloproteinase (MMP) inhibitors that also possess favorable solubility properties has proved to be especially challenging. A prior approach using collagen-model templates combined with transition state analogs produced a first generation of triple-helical peptide inhibitors (THPIs) that were effective in vitro against discreet members of the MMP family. These THPI constructs were also highly water soluble. The present study sought improvements in the first generation THPIs,...

Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels.

Transient receptor potential canonical 3/6/7 (TRPC3/6/7) are highly homologous receptor-operated non-selective cation channels. Despite their physiological significance, very few selective and potent agonists are available for functional examination of these channels. Using a cell-based high throughput screening approach, a lead compound with the pyrazolopyrimidine skeleton was identified as a TRPC6 agonist. Synthetic schemes for the lead and its analogs were established and structural-activity relationship...

CNS Physicochemical Property Space Shaped by a Diverse Set of Molecules with Experimentally Determined Exposure in the Mouse Brain.

Understanding the "limits and boundaries" of the central nervous system (CNS) property space is a critical aspect of modern CNS drug design. Medicinal chemists are often guided by the physicochemical properties of marketed CNS drugs, which are heavily biased toward "traditional" aminergic targets and commonly described as small lipophilic amines. This miniperspective describes the statistical analysis of the calculated physicochemical properties for a diverse set of ligands for mostly "nontraditional" CNS t...

Radiolabeled dibenzodiazepinone-type antagonists give evidence of dualsteric binding at the M2 muscarinic acetylcholine receptor.

The dualsteric ligand approach, aiming at ligands with improved subtype selectivity, has been increasingly applied to muscarinic receptors (MRs). In this article we present the synthesis and characterization of a M2R subtype-preferring radiolabeled dibenzodiazepinone-type antagonist ([(3)H]UNSW-MK259, [(3)H]19) and its homodimeric analog [(3)H]UR-AP060, ([(3)H]33). Saturation binding studies at the M2R, using the orthosteric antagonist atropine to determine unspecific binding, proved that the monomeric and ...

Molecular basis of substrate recognition and product release by the Klebsiella pneumoniae carbapenemase (KPC-2).

Carbapenem-resistant Enterobacteriaceae (CRE) are resistant to most β-lactam antibiotics due to production of the KPC-2 class A β-lactamase. Here we present the first product complex crystal structures of KPC-2 with β-lactam antibiotics, containing hydrolyzed cefotaxime and faropenem. They provide experimental insights into substrate recognition by KPC-2 and its unique cephalosporinase/carbapenemase activity. These structures also represent the first product complexes for a wild type serine β-lactamase,...

Prediction of antibiotic interactions using descriptors derived from compound molecular structure.

Combination antibiotic therapies are clinically important in the fight against bacterial infections, especially when infectious agent is resistant to single antibiotics. However, the search-space of drug combinations is large, making the identification of effective combinations a challenging task. Here, we present a computational framework that uses substructure profiles derived from drug molecular structures and predicts synergistic, additive, or antagonistic antibiotic combinations. We developed our model...

Chemically induced degradation of sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals).

Here we report the development of a proteolysis targeting chimera (PROTAC) based on the combination of the unique features of the sirtuin rearranging ligands (SirReals) as highly potent and isotype-selective Sirt2 inhibitors with thalidomide, a bona fide cereblon ligand. For the first time, we report the formation of a PROTAC by Cu(I)-catalyzed cycloaddition of a thalidomide-derived azide to an alkynylated inhibitor. This thalidomide-derived azide as well as the highly versatile linking strategy can be read...

N6-Substituted-5'-N-Methylcarbamoyl-4'-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation.

Potent and selective A3 adenosine receptor (AR) agonists were identified by replacement of 4'-oxo- or 4'-thionucleosides with bioisosteric selenium. Unlike previous agonists, 4'-seleno analogues preferred a glycosidic syn conformation and a South sugar puckering, as shown in the X-ray crystal structure of 5'-N-methylcarbamoyl derivative 3p. Among compounds tested, N6-3-iodobenzyl analogue 3d was found to be the most potent A3AR full agonist (Ki = 0.57 nM), which was ≥ 800- and 1900-fold selective for A1 a...

Structure-based design of highly selective inhibitors of the CREB binding protein bromodomain.

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB Binding Protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization, that paid particular attention to physiochemical properties, delivered chemical probes with desirable potency, selectivity and permeability attributes. An important feature of th...


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