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PubMed Journal Database | Journal of medicinal chemistry RSS

00:04 EST 17th January 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 2,600+ from Journal of medicinal chemistry

Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.

A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site resulting in potent FXIa inhib...

α-Ketothioamide derivatives: a promising tool to interrogate the phosphoglycerate dehydrogenase (PHGDH).

Given the putative role of PHGDH in cancer, development of inhibitors is required to explore its function. In this context, we established and validated a straightforward enzymatic assay suitable for high-throughput screening and we identified inhibitors with similar chemical scaffolds. Through a convergent pharmacophore approach, we synthesized α-ketothioamides that exhibit interesting in vitro PHGDH inhibition and encouraging cellular results. These novel probes may be use to understand the emerging biol...

Design, Synthesis and Biological Evaluation of Novel, Non-Brain Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis.

We report the design, synthesis and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid (CB1) receptor and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazoline carboximidamides were synthesized and evaluated in CB1 receptor (CB1R) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CB1 antagonist activities and iNOS inhibit...

Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-targeting Pyruvate Dehydrogenase Kinase Inhibitors.

Pyruvate dehydrogenase kinases 1-4 (PDK1-4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonyliso...

Optimization of 2-anilino 4-amino substituted quinazolines into potent antimalarial agents with oral in vivo activity.

Novel antimalarial therapeutics that target multiple stages of the parasites lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites equivalent to the known antimalarials, chloroquine and ...

Antagonizing NOD2 Signaling with Conjugates of Paclitaxel and Muramyl Dipeptide Derivatives Sensitizes Paclitaxel Therapy and Significantly Prevents Tumor Metastasis.

A non-cleavable paclitaxel (PTX) and N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) derivative conjugate, 22 (DY-16-43), and its analogues were prepared and characterized as antagonists of NOD2 signaling. This conjugate enhanced the anti-tumor and anti-metastatic efficacy of PTX in Lewis lung carcinoma (LLC) tumor-bearing mice. This work first describes a molecular strategy that enables the sensitization of a chemotherapeutic response via antagonizing NOD2 inflammatory signaling and suggests NOD2 antagonist...

Design and Synthesis of Novel Non Steroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Treatment of Rheumatoid Arthritis.

We report the synthesis of a series of 6- and 7-substituted coumarins with commercially available NSAIDs (13a-h and 14a-h) as potential tools for the treatment of RA and related diseases. All compounds resulted effective in inhibiting the RA over-expressed hCA IV with KIs comprised between 0.44-9.8 nM. Among the other RA relevant hCA isoforms (i.e. IX and XII), compounds 13f and 14a,b resulted commonly effective in inhibiting their activity. The antihyperalgesic activity of such compounds was assessed by me...

Water-soluble Ruthenium (II) Chiral Heteroleptic Complexes with Amoebicidal In vitro and In vivo Activity.

Three novel water soluble Ru(II) chiral heteroleptic coordination compounds [Ru(en)(pdto)]Cl2 (1), [Ru(gly)(pdto)]Cl (2) and [Ru(acac)(pdto)]Cl (3) where pdto= 1,8-bis-(2-pyridyl)-3,6-dithioctane, en= ethylendiamine, gly= glycinate and acac= acetylacetonate have been synthesised and have shown remarkable amoebicidal activity in vitro and in vivo. The crystal structures of compounds 1-3 are described. The in vitro IC50 values found are within nanomolar range (0.14, 0.12 and 0.06 µM for compounds 1, 2 and 3,...

Discovery of Potent Cyclophilin Inhibitors based on Structural Simplification of Sanglifehrin A.

Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl...

Total Syntheses and Biological Activities of Vinylamycin Analogs.

Natural depsipeptide vinylamycin was reported to be an antibiotic previously. Herein, we report vinylamycin to be active against K562 leukemia cells (IC50 = 4.86 μM), and be unstable in plasma (t1/2 = 0.54 h). A total of 24 vinylamycin analogs with modification of the OH group and chiral centers were generated via a combinatorial approach. The lead compound 1a was subsequently characterized as having: no anti-microbial activity, significantly higher plasma stability (t1/2 = 14.3 h), improved activity again...

Regulating the Master Regulator: Controlling Ubiquitination by Thinking Outside the Active Site.

The labeling of proteins with ubiquitin/ubiquitin-like (Ubl) proteins is crucial for several physiological processes and in the onset of various diseases. Recently, targeting ubiquitin protein labeling has shifted towards the use of allosteric mechanisms over classical activity-based approaches. Allosteric enzyme regulation offers the potential for greater selectivity and has demonstrated less susceptibility to acquired resistance often associated with active site inhibitors. Furthermore, the isoform divers...

Type I DNA Topoisomerases.

DNA topoisomerases constitute a large family of essential enzymes in all domains of life. Even though they share the general reaction chemistry and the ability to govern DNA topology and resolve strand entanglements during fundamental molecular processes, they are characterized by differences in structural organization, modes of enzymatic catalysis and biological functions. Moreover, hundreds of compounds are known to interfere with bacterial and/or eukaryotic enzymes, and some of them are effective drugs f...

Discovery of 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag) :An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) is described. Detailed profiling of a number of analogues resulted in the identification of 3c (APD811, Ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family, and a more modest 40- 50-fold selectivity over the EP3 receptor. In our hands, its p...

Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies.

The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluat...

Potent Inhibition of Nitric Oxide-Releasing Bifendate Derivatives against Drug-Resistant K562/A02 Cells In Vitro and In Vivo.

Multidrug resistance is a major obstacle to successful chemotherapy for leukemia. In this study, a series of nitric oxide (NO)-releasing bifendate derivatives (7a-n) were synthesized. Biological evaluation indicated that the most active compound (7a) produced relatively high levels of NO and significantly inhibited the proliferation of drug-resistant K562/A02 cells in vitro and in vivo. In addition, 7a induced the mitochondrial tyrosine nitration, and the intracellular accumulation of rhodamine 123 by inhib...

Design, Synthesis of Novel, Potent, Selective, Orally Bio-available Adenosine A2A Receptor Antagonists and Their Biological Evaluation.

Our initial structure-activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position lead to identification of compound 25 as a potent and selective A2A adenosine receptor (A2AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug des...

Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and their Pharmacologies.

Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acryl amide led to compound 71 with improvement of the antagonist activity (OX1R: Ki = 1.36 nM, OX2R: Not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in wate...

Tackling Fungal Resistance by Biofilm Inhibitors.

The high incidence and mortality of invasive fungal infections and serious drug resistance have become a global public health issue. The ability of fungal cells to form biofilms is an important reason for the emergence of severe resistance to most clinically available antifungal agents. Targeting fungal biofilm formation by small molecules represents a promising new strategy for the development of novel antifungal agents. This perspective will provide a comprehensive review of fungal biofilm inhibitors. In ...

The Difluoromethyl Bioisoster: Examining the "Lipophilic Hydrogen Bond Donor" Concept.

There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor which may act as a bioisostere of hydroxyl, thiol or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their drug-like properties; hydrogen bonding and lipophilicity were studied., The hydrogen bond acidity parameters A (0.085-0.126) were determined using Abraham's solute 1H NMR analysis. It was found that the difluoromethyl group acts a...

Development of the first Two-Pore Domain Potassium Channel TREK-1 (TWIK-Related K(+) Channel 1)-selective agonist possessing in vivo anti-nociceptive activity.

The TWIK-Related K(+) channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here we report the synthesis of a series of substituted acrylic acids (1-54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced ...

Modulating Mineralocorticoid Receptor with Non-steroid Antagonists. New Opportunities for the Development of Potent and Selective Ligands without Off-target Side-effects.

Steroidal mineralocorticoid receptor (MR) antagonists are used for treatment of a range of human diseases, but present challenging issues of complex chemical synthesis, undesirable physical properties and poor selectivity along with unwanted side effects. Therefore, there is a great interest in the discovery of non-steroidal ligands able to bind to the ligand-binding domain (LBD) of the MR, and recruit different coregulators to produce tissue-specific therapeutic effects. Several academic groups and pharmac...

SAR of the Antimalarial Ozonide Artefenomel (OZ439).

Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower Log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional func...

Discovery of Cell-Permeable O-GlcNAc Transferase Inhibitors via Tethering in Situ Click Chemistry.

O-GlcNAc transferase (OGT) is a key enzyme involved in dynamic O-GlcNAcylation of nuclear and cytoplasmic proteins similar to phosphorylation. Discovery of cell-permeable OGT inhibitors is significant to clarify the function and regulatory mechanism of O-GlcNAcylation. This will establish the foundation for the development of therapeutic drugs for relevant diseases. Here, we report two cell-permeable OGT inhibitors (APNT and APBT), developed from low-activity precursors (IC50 > 1 mM) via "tethering in situ ...

Carbon-11 and Fluorine-18 Radiolabeled Pyridopyrazinone Derivatives for Positron Emission Tomography (PET) Imaging of Phosphodiesterase-5 (PDE5).

The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy. PDE5 represents an important therapeutic and/or prognostic target, but noninvasive assessment of PDE5 expression is lacking. The purpose of this study was to develop and evaluate pyridopyrazinone derivatives labeled with carbon-11 or fluorine-18 as PDE5-specific PET tracers. In biodistribution studies, highest PDE5-spe...

The Discovery and Hit-to-Lead Optimization of Tricyclic Sulfonamides as Potent and Efficacious Potentiators of Glycine Receptors.

Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well as abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission of painful stimuli. Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic sulfonamides as allosteric GlyR potentiators. Initial optimization of high-throughput screening (HTS) hi...


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