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17:38 EDT 21st October 2014 | BioPortfolio

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Showing PubMed Articles 1–25 of 1,800+ from Journal of medicinal chemistry


Radiosynthesis and Evaluation of an (18)F-Labeled Positron Emission Tomography (PET) Radioligand for Metabotropic Glutamate Receptor Subtype 4 (mGlu4).

Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxo-isoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F. When finally formulated in 0.1 M citrate buffer (pH4) with 10% ethanol, the specific activity of [(18)F]3 at the end of synthesis (EOS) was ...


Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation In Vitro.

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis (OA) and therefore represents a target for drug development. As a result of high-throughput screening (HTS) and structure-activity relationship (SAR) studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding ...


Second-Generation Antibacterial Benzimidazole Ureas: Discovery of A Preclinical Candidate with Reduced Metabolic Liability.

ABSTRACT Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified a...


11H-Pyrido3',2':4,5pyrrolo3,2-ccinnoline and pyrido3',2':4,5pyrrolo1,2-c1,2,3 benzotriazine: two new ring systems with antitumor activity.

Derivatives of new ring systems 11H-pyrido[3',2':4,5]pyrrolo[3,2-c]cinnoline and pyrido[3',2':4,5]pyrrolo[1,2-c][1,2,3]benzotriazine were prepared from the key intermediates 2-(1H-pyrrolo[2,3-b]pyridin-2-yl)anilines in excellent yields (94-99%) and screened by the National Cancer Institute (NCI, Bethesda, USA), on about 60 human tumor cell lines derived from nine cancer cell types. Tested compounds exhibited antiproliferative activity against all the human cell lines showing comparable MG_MID range 0.74-1.1...

Tuesday 13th July 1096

Loratadine and analogs: Discovery and preliminary SAR of inhibitors of the amino acid transporter B0AT2.

B0AT2, encoded by the SLC6A15 gene, is a transporter for neutral amino acids that has recently been implicated in mood and metabolic disorders. It is predominantly expressed in the brain but little is otherwise known about its function. In order to identify inhibitors for this transporter we screened a library of different 3133 bioactive compounds. Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B0AT2 with an IC50 of 4 µM while being less active or...

Wednesday 11th February 1096

Targeting Nucleus DNA with a Cyclometalated Dipyridophenazine Ruthenium(II) Complex.

Recently, coordinatively saturated and substitutionally inert Ru(II) complexes have been investigated as anticancer agents.. Herein a cyclometalated Ru(II) complex, [Ru(bpy)(phpy)(dppz)]+, was found to be rapidly taken up by cancer cells, and nearly 90% of the complex accumulated in the nuclei of cancer cells after 2 h incubation. The anticancer activity of this complex was screened against a panel of cancer cell lines. Remarkably, it exhibit-ted IC50 values that were an order of magnitude lower than cispla...


Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase.

An affinity-based mass spectrometry screening technology was used to identify novel binders to both non-phosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both non-phosphorylated and phosphorylated ERK2, and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which demonstrated not only inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated ...


Inhibitory Activities of Propolis and its Promising Component, Caffeic Acid Phenethyl Ester, against Amyloidogenesis of Human Transthyretin.

Transthyretin (TTR) is a homo-tetrameric serum protein associated with amyloidoses such as familial amyloid polyneuropathy and senile systemic amyloidosis. The amyloid fibril formation of TTR can be inhibited through stabilization of the TTR tetramer by the binding of small molecules. In this study, we examined the inhibitory potency of caffeic acid phenethyl ester (CAPE) and its derivatives. Thioflavin T assay showed that CAPE suppressed the amyloid fibril formation of TTR. Comparative analysis of the inhi...


Biased multicomponent reactions to develop novel bromodomain inhibitors.

BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemi...


Coordination of hydroxyquinolines to a ruthenium bis-dimethyl-phenanthroline scaffold radically improves potency for potential as antineoplastic agents.

A series of ruthenium coordination complexes containing hydroxyqinoline ligands were synthesized that exhibited radically improved potencies up to 85-fold greater than clioquinol, a known cytotoxic compound. The complexes were also >100-fold more potent than clioquinol in a tumor spheroid model, with values similar to currently used chemotherapeutics for the treatment of solid tumors. Cytotoxicity occurs through rapid processes that induce apoptosis, but appear to be mediated by cell-cycle independent mecha...

Sunday 31st August 1095

Fragment-based screening of the bromodomain of ATAD2.

Cellular and genetic evidence suggest that inhibition of ATAD2 could be a useful strategy to treat several types of cancer. To discover small molecule inhibitors of the bromodomain of ATAD2, we used a fragment-based approach. Fragment hits were identified using NMR spectroscopy, and ATAD2 was crystallized with three of the hits identified in the fragment screen.


Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition.

Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to...


Structural insights on carbonic anhydrase inhibitory action, isoform selectivity and potency of sulfonamides and coumarins incorporating arylsulfonylureido groups.

Sulfonamides and coumarins incorporating arylsulfonylureido tails were prepared and assayed as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC Some derivatives incorporating 3-pyridine-sulfonamide and arylsulfonylureoido fragments were low nanomolar inhibitors of isoforms CA II and XII (upregulated or overexpressed in glaucoma), and showed effective in vivo intraocular pressure lowering effects in an animal model of the disease, which were several times better compared to those of the a...

Friday 9th July 1091

A Two-pronged Attack: Dual Inhibition of Plasmodium falciparum M1 and M17 Metalloaminopeptidases by a Novel Series of Hydroxamic acid-based Inhibitors.

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection, and have been validated as potential antimalarial targets. Using compound-bound crystal str...

Thursday 12th March 1090

Importance of Purity Evaluation and the Potential of Quantitative (1)H NMR as a Purity Assay.

In any biomedical and chemical context, a truthful description of chemical constitution requires coverage of both structure and purity. This qualification affects all drug molecules, regardless of development stage (early discovery to approved drug) and source (natural product or synthetic). Purity assessment is particularly critical in discovery programs and whenever chemistry is linked with biological and/or therapeutic outcome. Compared with chromatography and elemental analysis, quantitative NMR (qNMR) ...

Saturday 11th January 1089

Substitution of the Lys Linker with the β-Ala Linker Dramatically Decreased the Renal Uptake of Tc-99m-Labeled Arg-X-Asp-Conjugated and X-Ala-Asp-Conjugated α-Melanocyte Stimulating Hormone Peptides.

The purpose of this study was to examine whether the substitution of the Lys linker with the β-Ala could reduce the renal uptake of (99m)Tc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated alpha-melanocyte stimulating hormone (α-MSH) peptides. RSD-β-Ala-(Arg(11))CCMSH {c[Arg-Ser-Asp-DTyr-Asp]-β-Ala-Cys-Cys-Glu-His-DPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-β-Ala-(Arg(11))CCMSH, RVD-β-Ala-(Arg(11))CCMSH, RAD-β-Ala-(Arg(11))CCMSH, NAD-β-Ala-(Arg(11))CCMSH and EAD-β-Ala-(Arg(11))CCMSH peptides were s...


Synthesis and biological evaluation of novel peptide BF2 as an antibacterial agent against clinical isolates of Vancomycin-Resistant Enterococci.

Enterococci are the leading cause of nosocomial infections worldwide and acquired resistance to a variety of antibiotics. Antimicrobial peptides are representing a promising molecule against the antibiotic resistance in bacteria and indispensable component of innate immune system. The aim of the study was to develop an antimicrobial peptide against vancomycin resistant enterococci (VRE). We have designed a series of peptides based on Sapecin B as template. In vitro antibacterial study of synthetic peptide B...


Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold - SAR and In Vivo Characterization.

The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction and favorable pharm...


Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists.

Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of the metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subs...


Synthesis and Preclinical Evaluation of 2-(2-Furanyl)-7-2-4-4-(2-(11)Cmethoxyethoxy)phenyl-1-piperazinylethyl7H-pyrazolo4,3-e1,2,4triazolo1,5-cpyrimidine-5-amine ((11)CPreladenant) as a PET Tracer for the Imaging of Cerebral Adenosine A2A Receptors.

2-(2-Furanyl)-7-[2-[4-[4-(2-[(11)C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine [(11)C]-3 ([(11)C]Preladenant) was developed for mapping cerebral adenosine A2A receptors (A2ARs) with PET. The tracer was synthesized in high specific activity and purity. Tissue distribution was studied by PET imaging, ex vivo biodistribution (BD) and in vitro autoradiography (ARG) experiments. Regional brain uptake of [(11)C]-3 was consistent with known A2ARs distributio...


DNA Repair and Redox Activities and Inhibitors of Apurinic/Apyrimidinic Endonuclease 1/Redox Effector Factor-1 (APE1/Ref-1): A Comparative Analysis and their Scope and Limitations toward Anticancer Drug Development.

The apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1) is a multifunctional enzyme involved in DNA repair and activation of transcription factors through its redox function. The evolutionarily conserved C- and N-termini are involved in these functions independently. It is also reported that the activity of APE1/Ref-1 abruptly increases several fold in various human cancers. The control over the outcomes of these two functions is emerging as a new strategy to combine enhanced DNA damag...


Oligonucleotide Analogues as Modulators of the Expression and Function of non-coding RNAs (ncRNAs) : Emerging Therapeutics Applications.

ncRNAs are emerging as key regulators of physiological and pathological processes and therefore have been identified as pharmacological targets and as markers for some diseases. Oligonucleotide analogues represent so far the most widely employed tool for the modulation of the expression of ncRNAs. In this perspective we briefly describe most of the known classes of ncRNAs and then we discuss the design and the applications of oligonucleotide analogues for their targeting. The effect of modifications of the ...


Design, Synthesis, and Antibacterial Properties of Dual-Ligand Inhibitors of Acetyl-CoA Carboxylase.

There is an urgent demand for the development of new antibiotics due to the increase in drug-resistant pathogenic bacteria. A novel target is the multifunctional enzyme acetyl-CoA carboxylase, which catalyzes the first committed step in fatty acid synthesis, and consists of two enzymes: biotin carboxylase and carboxyltransferase. Covalently attaching known inhibitors against these enzymes with saturated hydrocarbon linkers of different lengths generated dual-ligand inhibitors. Kinetic results revealed the d...


Discovery of Potent and Selective Sirtuin 2 (SIRT2) Inhibitors Using a Fragment-Based Approach.

Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD(+)-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naph...


Molecular simulations with solvent competition quantify water displaceability and provide accurate interaction maps of protein binding sites.

Binding sites present well-defined interaction patters that putative ligands must meet. Knowing them is essential to guide structure-based drug discovery projects. However, complex aspects of molecular recognition - such as protein flexibility or the effect of aqueous solvation - hinder accurate predictions. This is particularly true for polar contacts, which are heavily influenced by the local environment and the behavior of discrete water molecules. Here we present and validate MDmix (Molecular Dynamics s...

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