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PubMed Journal Database | Journal of medicinal chemistry RSS

22:35 EST 11th February 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 2,300+ from Journal of medicinal chemistry

Discovery and characterization of biased allosteric agonists of the chemokine receptor CXCR3.

In this work we report a design, synthesis and detailed functional characterization of unique strongly biased allosteric agonists of CXCR3 that contain tetrahydroisoquinoline carboxamide cores. The compound 11 (FAUC1036) is the first strongly biased allosteric agonist of CXCR3 that selectively induces weak chemotaxis, leads to receptor internalization and the β-arrestin 2 recruitment with potency comparable to that of the chemokine CXCL11 without any activation of G proteins. A subtle structural change (ad...

Lanthanides: Applications in Cancer Diagnosis and Therapy.

Lanthanide complexes are of increasing importance in cancer diagnosis and therapy, owing to the versatile chemical and magnetic properties of the lanthanide-ion 4f electronic configuration. Following the first implementation of gadolinium(III)-based contrast agents in magnetic resonance imaging in the 1980s, lanthanide-based small molecules and nanomaterials have been investigated as cytotoxic agents and inhibitors, in photodynamic therapy, radiation therapy, drug/gene delivery, biosensing, and bioimaging. ...

Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues.

A series of analogues of the AMPA receptor agonist BnTetAMPA (5b) was synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus lævis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three lig...

Conopeptide-derived κ-opioid agonists (conorphins): potent, selective and metabolic stable dynorphinA mimetics with anti-nociceptive properties.

Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins, are defined by a hydrophobic benzo-prolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic resi...

Synthesis and In Vitro Studies of a Series of Carborane-containing Boron Dipyrromethenes (BODIPYs).

A series of seven BODIPYs functionalized with ortho-carborane groups at the 8(meso) or 5(α) position, were synthesized and characterized by NMR, HRMS, HPLC, and in the case of 2b and 5b, by X-ray analysis. The BODIPYs exhibited low dark- and photo-toxicities toward human glioma T98G cells, and their cellular uptake varied significantly with 5b accumulating the most and 7 the least. All BODIPYs localized mainly within the cell ER. The BODIPYs showed higher permeabilities than lucifer yellow across human hCM...

Thiazolino 2-pyridone amide inhibitors of Chlamydia trachomatis infectivity.

The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Here in, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 ≤100 nM) in attenuating infectivity across multiple serovars of C. ...

Quadruplex Nucleic Acids as Novel Therapeutic Targets.

Quadruplex-forming sequences are widely prevalent in human and other genomes, including bacterial ones. These sequences are over-represented in eukaryotic telomeres, promoters and 5' untranslated regions. They can form quadruplex structures, which may be transient in many situations in normal cells since they can be effectively resolved by helicase action. Mutated helicases in cancer cells are unable to unwind quadruplexes, which are impediments to transcription, translation or replication, depending on the...

Optimization by Molecular Fine Tuning of Dihydro-β-agarofuran Sesquiterpenoids as Reversers of P-glycoprotein-Mediated Multidrug Resistance.

P-glycoprotein (P-gp) plays a crucial role in the development of multidrug resistance (MDR), a major obstacle for successful chemotherapy in cancer. Herein, we report on the development of a natural-product-based library of 81 dihydro-β-agarofuran sesquiterpenes (2 -82) by optimization of the lead compound 1. The compound library was evaluated for its ability to inhibit P-gp-mediated daunomycin efflux in MDR cells. Selected analogues were further analyzed for their P-gp inhibition constant, intrinsic toxic...

Epigenetics: Novel Therapeutics Targeting Epigenetics.

Discovery of a Potent Class I Protein Arginine Methyltransferase Fragment Inhibitor.

Protein methyltransferases (PMTs) are a promising target class in oncology and other disease areas. They are composed of SET domain methyltransferases and structurally unrelated Rossman-fold enzymes that include protein arginine methyltransferases (PRMTs). In the absence of a well-defined medicinal chemistry tool-kit focused on PMTs, most current inhibitors were identified by screening large and diverse libraries of leadlike molecules. So far, no successful fragment-based approach was reported against this ...

Engineering of a novel simplified human insulin-like peptide 5 agonist.

Insulin-like peptide 5 (INSL5) has recently been discovered as only the second orexigenic gut hormone after ghrelin. As we have previously reported, INSL5 is extremely difficult to assemble and oxidize into its two-chain three-disulfide structure. The focus of this study was to generate structure-activity relationships (SAR) of INSL5 and use it to develop a potent and simpler INSL5 mimetic with RXFP4 agonist activity. A series of human and mouse INSL5 (hINSL5/mINSL5) analogues were designed and chemically s...

Mimicking of arginine by functionalized Nω-carbamoylated arginine as a new broadly applicable approach to labeled bioactive peptides: high affinity angiotensin, neuropeptide Y, neuropeptide FF and neurotensin receptor ligands as examples.

Derivatization of biologically active peptides by conjugation with fluorophores or radionuclide-bearing moieties is an effective and commonly used approach to prepare molecular tools and diagnostic agents. Whereas lysine, cysteine and N-terminal amino acids have been mostly used for peptide conjugation, we describe a new, widely applicable approach to peptide conjugation based on the nonclassical bioisosteric replacement of the guanidine group in arginine by a functionalized carbamoylguanidine moiety. Four ...

Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes.

Three novel families of A2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2(1H)-one chemotype. The most appealing series' contain imidazole, 1,2,4-triazole or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled to identify a highly potent (3.49 nM) A2B ligand that exhibits complete selectivity toward A1, A2A and A3 receptors. The results of functional cAMP experiments confirmed...

Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation.

The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.

Discovery of the First Environment-Sensitive Near-Infrared (NIR) Fluorogenic Ligand for α1-Adrenergic Receptors Imaging in vivo.

Fluorescent ligands are gaining popularity as tools to aid GPCR research. Nontheless, in vivo application of such tools is hampered due to their short excitation wavelengths in the visible range and lack of fluorogenic switch. Here we report the discovery of fluorescent ligands (3a-f) for α1-adrenergic receptors (α1-ARs) by conjugating the environment-sensitive fluorophore, cyane 5 (Cy5), with the quinazoline pharmacophore. Among them, the conjugated compound 3a, with acylated piperazin and the shortest c...

Novel Water-Soluble Amphotericin B-PEG Conjugates with Low Toxicity and Potent in Vivo Efficacy.

Systemic fungal infections are an increasingly prevalent health problem, especially among immunocompromised patients. Antifungal drug development lags far behind in comparison to other types of antimicrobial drugs. Current commercially available antifungals are limited by their insufficient potency, side effects, drug-drug interactions, developing drug-resistance, and narrow formulation options. Here, we report the preparation and evaluation of two novel PEG amide conjugates of amphotericin B (AMB (1)): AB1...

Discovery of (R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-1,2,4triazolo4,3-apyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.

Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable pre-clinical pharmacokinetics, significant inhibition of MET phosphorylation in mice and robust tumor growth inhibition in a MET-dependent mouse efficacy model.

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS.

HIV-1 protease inhibitors continue to play an important role in the treatment of HIV/AIDS, transforming this deadly ailment into a more manageable chronic infection. Over the years, intensive research has led to a variety of approved protease inhibitors for the treatment of HIV/AIDS. In this review, we outline current drug design and medicinal chemistry efforts toward the development of next-generation protease inhibitors beyond the currently approved drugs.

The Discovery of Narrow Spectrum Kinase Inhibitors: New Therapeutic Agents for the Treatment of COPD and Steroid-Resistant Asthma.

The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease (COPD) is reported. The pharmacological strategy was based upon the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.

Ligand-Protein Affinity Studies using Long-Lived States of Pairs of Fluorine-19 Nuclei.

The lifetimes TLLS of long-lived states or TLLC of long-lived coherences can be used for the accurate determination of dissociation constants of weak protein-ligand complexes. The remarkable contrast between signals derived from LLS or LLC in free and bound ligands can be exploited to search for weak binders with large dissociation constants KD > 1 mM that are important for fragment-based drug discovery but may escape detection by other screening techniques. Alternatively, the high sensitivity of the propos...

A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation.

Sirtuins are important regulators of lysine acylation, which is implicated in cellular metabolism and transcriptional control. This makes the sirtuin class of enzymes interesting targets for development of small molecule probes with pharmaceutical potential. To achieve detailed profiling and kinetic insight regarding sirtuin inhibitors, it is important to have access to efficient assays. In this work, we report readily synthesized fluorogenic substrates enabling enzyme-economical evaluation of SIRT2 inhibit...

Characterization of multi-substituted Corticotropin Releasing Factor (CRF) peptide antagonists (Astressins).

CRF mediates numerous stress-related endocrine, autonomic, metabolic and behavioral responses. We present the synthesis, chemical and biological properties of astressin B analogues {cyclo(30-33)[DPhe12,Nle21,38,CαMeLeu 27,40,Glu30,Lys33]-Acetyl-h/r-CRF(9-41)}. Out of 37 novel peptides, 17 (2, 4, 6- 8, 10, 11, 16, 17, 27, 29, 30, 32-36) and 16 (3, 5, 9, 12-15, 18, 19, 22-26, 28, 31) had ki to CRF receptors in the high picomolar and low nanomole ranges, respectively. Peptides 1, 2 and 11 inhibited h/rCRF and...

Identification of Novel GPR55 Modulators Using Cell-Impedance-Based Label-Free Technology.

The orphan G protein-coupled receptor GPR55 has been proposed as a novel receptor of the endocannabinoid system. However, the validity of this categorization is still under debate mainly due to the lack of potent and selective agonists and antagonists of GPR55. Binding assays are not yet available for GPR55 screening and GPR55 signal pathways discrepancies have been reported. In this context, we have designed and synthesized novel GPR55 ligands based on a chromenopyrazole scaffold. Appraisal of GPR55 activi...

Potent Mu-Opioid Receptor Agonists from Cyclic Peptides Tyr-cD-Lys-Xxx-Tyr-Gly: Synthesis, Biological and Structural Evaluation.

To optimize the structure of a mu-opioid receptor ligand, analogs H-Tyr-c[D-Lys-Xxx-Tyr-Gly] were synthesized and their biological activity were tested. The analog containing a Phe(3) was identified not only exhibiting binding affinity 14-fold higher than the original hit but also producing agonist activity 3-fold more potent than morphine. NMR study suggested that a trans conformation at D-Lys(2)-Xxx(3) is crucial for these cyclic peptides to maintain high affinity, selectivity, and functional activity tow...

Discovery of 2-((3-amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a potent, selective and orally available BCR-ABL/SRC/p38 kinase inhibitor for Chronic Myeloid Leukemia.

Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL auto-phosphorylation (EC50 about 100 nM) and downstream mediators such as STAT5, Crkl and ERK's phosphorylati...


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