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PubMed Journal Database | Journal of medicinal chemistry RSS

21:06 EDT 29th May 2016 | 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 2,400+ from Journal of medicinal chemistry

β-Lactamases: Why and How.

The targets of β-lactam antibiotics are bacterial DD-peptidases that catalyze the final steps of peptidoglycan biosynthesis. Bacterial resistance to β-lactams is achieved by the production of β-lactamases, enzymes that catalyze β-lactam hydrolysis. Structural studies of both of these groups of enzymes, their substrates and of β-lactams have led to the conclusion that β-lactamases have evolved from a DD-peptidase ancestor. Thus, the active sites of DD-peptidases and serine β-lactamases are very simila...

Benzyl (11)CHippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice.

Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several (11)C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding (11)C-labeled organic acids in target tissues. Among the compoun...

Tetrahydroisoquinoline-derived urea and 2,5-diketopiperazine derivatives as selective antagonists of the transient receptor potential melastatin 8 (TRPM8) channel receptor and anti-prostate cancer agents.

Tetrahydroisoquinoline derivatives containing embedded urea functions were identified as selective TRPM8 channel receptor antagonists. Structure activity relationships were investigated, with the following conclusions: (a) The urea function and the tetrahydroisoquinoline system are necessary for activity. (b) Bis(1-aryl-6,7dimethoxy-1,2,3,4-tetrahydroisoquinolyl)ureas are more active than compounds containing one tetrahydroisoquinoline ring and than an open phenetylamine ureide. (c) Trans compounds are more...

Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development.

The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well a...

Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability.

Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encoun...

Structure-Activity Relationship of 18F-labeled phosphoramidate peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-targeted inhibitor analogues for PET imaging of prostate cancer.

A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also co-crystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50's ranging from 0.4-1.3nM. In vitro whole cell assays showed bi...

High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C-terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination and Radiolabeling.

The diastereomeric mixture of D/L-2,7-diaminooctanedioyl-bis(YRLRY-NH2) (BVD-74D, 2) was described in the literature as a high affinity Y4 receptor agonist. Here we report on the synthesis and pharmacological characterization of the pure diastereomers (2R,7R)- and (2S,7S)-2 and a series of homo- and heterodimeric analogues in which octanedioic acid was used as an achiral linker. To investigate the role of the Arg residues, one or two arginines were replaced by Ala. Moreover, N(ω)-(6-aminohexylaminocarbonyl...

Structure-Based Design of Potent Nicotinamide Phosphoribosyltransferase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities.

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) has the potential to directly limit NAD production in cancer cells and is an effective strategy for cancer treatment. Using a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of NAMPT. Several designed compounds showed promising antiproliferative activities in vitro. (E)-N-(5-((4-(((2-(1H-indol-3-yl)ethyl)(isopropyl)amino)methyl)phenyl)amino)pentyl)-3-(pyridin-3-yl)acrylamide, 30, bearing an indole moiety ...

Structure-Based Design of Tetrahydroisoquinoline-7-Carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors.

The structure-based design of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as selective DDR1 inhibitors is reported. One of the representative compounds, 6j, binds to DDR1 with a Kd value of 4.7 nM and suppresses its kinase activity with an IC50 value of 9.4 nM, but it is significantly less potent for a panel of 400 non-mutated kinases. 6j also demonstrated rea-sonable pharmacokinetic properties and a promising oral therapeutic effect in a bleomycin-induced mouse pulmonary fibrosis model.

Diving into the water: Inducible binding conformations for BRD4, TAF1(2), BRD9, and CECR2 bromodomains.

The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient non-selective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing towards the conserved bromodomain water pocket, and two distinct binding conformation...

Design, Synthesis and Preclinical Evaluation of 4-Substituted-5-methyl-furo2,3-dpyrimidines as Microtubule Targeting Agents that are Effective against Multidrug Resistant Cancer Cells.

The design, synthesis and biological evaluations of eight 4-substituted 5-methyl-furo[2,3-d]pyrimidines are reported. Synthesis involved N4-alkylation of N-aryl-5-methylfuro[2,3-d]pyrimidin-4-amines, obtained from Ullmann coupling of 4-amino-5-methylfuro[2,3-d]pyrimidine and appropriate aryl iodides. Compounds 3, 4 and 9 showed potent microtubule depolymerizing activities, while compounds 6‒8 had slightly lower potency. Compounds 4, 6, 7 and 9 inhibited tubulin assembly with IC50 values comparable to that...

Design, Synthesis, and Evaluation of in Vitro and In Vivo Anticancer Activity of 4-Substituated Coumarins: A Novel Class of Potent Tubulin Polymerization Inhibitors.

In this paper, a series of novel 4-substituated coumarin derivatives were synthesized and evaluated for their antiproliferative activity in vitro. Several compounds exhibited significant antiproliferative activity toward a panel of tumor cell lines at sub nanomolar IC50 values. Selected compounds were evaluated by cytotoxicity, microtubule reassemble using immunofluorescence and in vivo antitumor activity in C26 and H460 tumor xenografts models. Further investigation revealed that selected compound 65 showe...

Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase.

In order to develop novel treatments for type II diabetes and dyslipidemia we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.

Design, synthesis and characterization of cyclic peptidomimetics of the inducible nitric oxide synthase (iNOS) binding epitope that disrupt the protein-protein interaction involving SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) and iNOS.

SPSB2 knock-out mice have been found to exhibit prolonged expression of iNOS in macrophage cells and enhanced killing of persistent pathogens, suggesting that inhibitors of SPSB2-iNOS interaction have potential as novel anti-infectives. In this study, we describe the design, synthesis and characterization of cyclic peptidomimetic inhibitors of the SPSB2-iNOS interaction constrained by organic linkers to improve stability and druggability. SPR, ITC and 19F NMR analyses revealed that the most potent cyclic pe...

Non-toxic metal-cyclam complexes, a new class of compounds with potency against drug-resistant Mycobacterium tuberculosis.

Tuberculosis (TB) accounted for 1.5 million deaths in 2014 and new classes of anti-TB drugs are required. We report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. These compounds inhibit intracellular growth of Mycobacterium tuberculosis, are non-toxic to human cell lines and are active against multidrug-resistant M. tuberculosis strains, indicating a distinct mode of action. These compounds warrant further appraisal as no...

Synthesis, Radiolabelling and Biological Evaluation of 5-Hydroxy-218FFluoroalkyl-Tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging.

Aiming at developing mechanism-based amino acid 18F-PET tracers for tumor imaging, we synthesized two 18F-labelled analogues of 5-hydroxy-L-[β-11C]tryptophan ([11C]5HTP) whose excellent in vivo performance in neuroendocrine tumors is mainly attributed to its decarboxylation by aromatic amino acid decarboxylase (AADC), an enzyme overexpressed in these malignancies. Reference compounds and precursors were synthesized following multistep synthetic approaches. Radiosynthesis of tracers was accomplished in good...

Effects of N-Substitutions on the Tetrahydroquinoline (THQ) core of Mixed-Efficacy μ-Opioid Receptor (MOR)/ δ-Opioid Receptor (DOR) Ligands.

N-acetylation of the tetrahydroquinoline (THQ) core of a series of µ-opioid receptor (MOR) agonist/ δ-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10...

Synthesis and biological evaluation of 4-Anilino-quinazolines and -quinolines as inhibitors of Breast Cancer Resistance Protein (ABCG2).

Chemotherapeutic treatment of cancer often fails due to overexpression of ATP-binding cassette (ABC) transport proteins, like ABCG2, triggering active efflux of various structurally unrelated drugs. This so-called multidrug resistance (MDR) may be reversed by selective, potent and non-toxic inhibitors of ABCG2. As only a few potent inhibitors are known, new compounds based on a 4-substituted-2-phenylquinazoline scaffold were investigated. Substitution with hydroxy, cyano, nitro, acetamido and fluoro led to ...

Synthesis, Evaluation, and Mechanism Study of Novel Indole-chalcone Derivatives Exerting Effective Anti-tumor Activity Through Microtubule Destabilization In vitro and In vivo.

Twenty-nine novel indole-chalcone derivatives were synthesized and evaluated for antiproliferative activity. Among them, 14k exhibited most potent activity, with IC50 values of 3 - 9 nM against six cancer cells, which displayed a 3.8-8.7 - fold increase in activity when compare with compound 2. Further investigation revealed 14k was a novel tubulin polymerization inhibitor binding to the colchicine site. Its low cytotoxicity towards normal human cells and nearly equally potent activity against drug-resistan...

Novel cephalosporins selectively active on non-replicating Mycobacterium tuberculosis.

We report two series of novel cephalosporins that are bactericidal to Mycobacterium tuberculosis alone of the pathogens tested, that only kill M. tuberculosis when its replication is halted by conditions resembling those believed to pertain in the host, and whose bactericidal activity is not dependent on or enhanced by clavulanate, a β-lactamase inhibitor. The two classes of cephalosporins bear an ester or, alternatively, an oxadiazole isostere, at C-2 of the cephalosporin ring system, a position that is a...

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.

In the treatment of EML4-ALK+ non-small-cell lung cancer (NSCLC), secondary mutations within the anaplastic lymphoma kinase (ALK) kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine...

PEGylated bis-sulfonamide carbonic anhydrase inhibitors can efficiently control the growth of several carbonic anhydrase IX-expressing carcinomas.

A series of aromatic/heterocyclic bis-sulfonamides were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores, coupled with either ethyleneglycol oligomeric or polymeric diamines to yield bis-sulfonamides with short or long (polymeric) linkers. Testing of novel inhibitors and their precursors against a panel of membrane-bound CA isoforms, including tumor-overexpressed CA IX and CA XII and cytosolic isozymes, identified nanomolar-potent inhibitors ag...

2-(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists.

Constitutive androstane receptor (CAR) is a key regulator of xenobiotic and endobiotic metabolism. Together with Pregnane X (PXR) and Aryl hydrocarbon (AHR) receptors, it is referred to as "xenobiotic receptor". The unique properties of human CAR, such as its high constitutive activity, both direct (ligand-binding domain-dependent) and indirect activation have hindered the discovery of direct selective human CAR ligands. Herein, we report a novel class of direct human CAR agonists in a group of 2-(3-methoxy...

Chlorin p6-based Water-soluble Amino Acid Derivatives as Potent Photosensitizers for Photodynamic Therapy.

The development of novel photosensitizer with high phototoxicity, low dark-toxicity and good water solubility is a challenging task for photodynamic therapy (PDT). A series of chlorin p6-based water-soluble amino acid conjugates were synthesized and investigated for antitumor activity. Among them, aspartylchlorin p6 dimethylester (7b) showed highest phototoxicity against melanoma cells with weakest dark-toxicity, which was more phototoxic than verteporfin while with less dark-toxicity. It also exhibited bet...

5'-Substituted amiloride derivatives as allosteric modulators binding in the sodium ion pocket of the adenosine A2A receptor.

The sodium ion site is an allosteric site conserved amongst many G protein-coupled receptors (GPCRs). Amiloride 1 and 5-(N,N-hexamethylene)amiloride 2 (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high resolution X-ray crystal structure of the human adenosine A2A receptor (hA2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report th...


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