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PubMed Journal Database | Journal of medicinal chemistry RSS

03:55 EST 20th February 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

Discovery and Preclinical Characterization of 3-((4-(4-chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications.

Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as potential pharmacotherapy for a number of psychiatric diseases including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the min...

Discovery and Development of 1-(2-Bromophenyl)sulfonyl-5-methoxy-3-(4-methyl-1-piperazinyl)methyl-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT6) Receptor Antagonist for Potential Treatment of Alzheimer's Disease.

Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT6R) antagonists resulted in identification of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (5al, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HT6R (Ki = 2.04 nM) and selectivity over 100 target sites which include receptors, enzymes, peptides, growth factors, ion chan...

Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase.

The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into non-skeletal tissues. Rece...

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase.

Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the en...

Target Elucidation by Co-crystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium Falciparum (PfNDH2) with Small Molecule to Eliminate Drug-Resistant Malaria.

Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new anti-malarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for anti-malarial drug development. However, the absence of structural information of PfNDH2 limited rational drug design and further development. Herein, we report high...

Drug Discovery Targeting Bromodomain-Containing Protein 4 (BRD4).

BRD4, the most extensively studied member of BET family, is an epigenetic regulator that localizes to DNA via binding acetylated histones and controls the expression of therapeutically important gene regulatory networks through recruiting transcription factors to form mediator complexes, phosphorylating RNA polymerase II and by its intrinsic histone acetyltransferase activity. Disrupting the protein-protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in...

A drug of such damned nature . Challenges and opportunities in translational platinum drug research.

The platinum-based anti-cancer agents cisplatin, carboplatin and oxaliplatin, represent a spectacular translational science achievement. The basic research observations that led to the discovery of Pt complexes as DNA-binding agents that elicit cell arrest, the pre-clinical tumor regression studies, and the inorganic medicinal chemistry that led to clinical implementation of effective platinum complexes in the clinic, have fueled multi-disciplinary research into platinum-based drugs. While the successes are...

Room temperature neutron crystallography of drug resistant HIV-1 protease uncovers limitations of X-ray structural analysis at 100K.

HIV-1 protease inhibitors are crucial for treatment of HIV-1/AIDS, but their effectiveness is thwarted by rapid emergence of drug resistance. To better understand binding of clinical inhibitors to resistant HIV-1 protease, we used room-temperature joint X-ray/Neutron (XN) crystallography to obtain an atomic-resolution structure of the protease triple mutant (V32I/I47V/V82I) in complex with amprenavir. The XN structure reveals a D+ ion located midway between the inner Oδ1 oxygen atoms of the catalytic aspar...

Discovery of an Inhibitor of the Proteasome Subunit Rpn11.

The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn(2+)-dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that...

Design, synthesis, structure-activity relationship studies, and three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling of a series of O-biphenyl carbamates as dual modulators of dopamine D3 receptor and fatty acid amide hydrolase.

We recently reported molecules designed according to the multi-target-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promisin...

Targeting Bacillosamine Biosynthesis in Bacterial Pathogens: Development of Inhibitors to a Bacterial Amino-Sugar Acetyltransferase from Campylobacter jejuni.

The glycoproteins of selected microbial pathogens often include highly modified carbohydrates such as 2,4-diacetamidobacillosamine (diNAcBac). These glycoconjugates are involved in host cell interactions and may be associated with the virulence of medically-significant Gram-negative bacteria. In light of genetic studies demonstrating the attenuated virulence of bacterial strains in which modified carbohydrate biosynthesis enzymes have been knocked out, we are developing small molecule inhibitors of selected...

Expeditious Lead Optimization of Isoxazole-Containing Influenza A Virus M2-S31N Inhibitors Using the Suzuki-Miyaura Cross-Coupling Reaction.

The existence of multidrug-resistant influenza viruses, coupled with the continuously antigenic shift and antigenic drift of influenza viruses, necessitates the development of the next-generation of influenza antivirals. As the AM2-S31N mutant persists in more than 95% of current circulating influenza A viruses, targeting the AM2-S31N proton channel appears to be a logical and valid approach to combating drug resistance. Starting from compound 1, an isoxazole compound with potent AM2-S31N channel blockage a...

Transition State-Based Sialyltransferase Inhibitors: Mimicking Oxocarbenium Ion by Simple Amide.

In the new transition-state-based sialyltransferase inhibitors, an amide group was placed at the corresponding C-2 position of CMP-sialic acid to mimic the geometry and charge distribution in the transition-state, and simple aromatic or aliphatic rings were used instead of sialic acid moiety. All synthetic compounds exhibited excellent α(2-6)-sialyltransferase inhibition, resulting in up to a 2600-fold higher affinity for the enzyme than CMP-Neu5Ac, suggesting that amide is a key element for simulating tra...

A novel potent anticancer compound optimized from a natural oridonin scaffold induces apoptosis and cell cycle arrest through the mitochondrial pathway.

The cytotoxicity of the natural ent-kaurene diterpenoid, oridonin, has been extensively studied. However, the application of oridonin for cancer therapy was hampered primarily by its moderate potency. In this study, a series of oridonin A-ring modified analogues, and their derivatives bearing various substituents on 14-OH position, were designed, synthesized and evaluated for anticancer efficacy. Some of the derivatives were significantly more potent than oridonin against both drug-sensitive and drug-resist...

Discovery of Novel Disruptor of Silencing Telomeric 1-Like (DOT1L) Inhibitors using a Target-specific Scoring Function for the S-adenosyl-L-methionine (SAM)-dependent Methyltransferase Family.

The disruptor of telomeric silencing 1-like (DOT1L) protein is a histone H3K79 methyltransferase that plays a key role in transcriptional elongation and cell cycle regulation and is required for the development and maintenance of MLL-rearranged mixed lineage leukemia. Much effort has been dedicated towards discovering novel scaffold DOT1L inhibitors using different strategies. Here, we report the development and application of a target-specific scoring function, the SAM score, for S-adenosyl-L-methionine (S...

Structural Analysis of Chemokine Receptor-Ligand Interactions.

This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9 and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors wit...

Identification of Novel Triazole-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors Endowed with Anti-Proliferative and Anti-Inflammatory Activity.

Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target as it is over-expressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in a xenograft and in allogra...

Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2) Inhibitors for the Treatment of Memory Disorders.

A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2 inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, increased potency of...

Full sequence amino acid scanning of θ-defensin RTD-1 yields a potent anthrax lethal factor protease inhibitor.

θ-Defensin RTD-1 is a non-competitive inhibitor of anthrax lethal factor (LF) protease (IC50 = 390 ± 20 nM, Ki = 365 ± 20 nM) and a weak inhibitor of other mammalian metalloproteases such as TNFα converting enzyme (TACE) (Ki = 4.45 ± 0.48 µM). Using full sequence amino acid scanning in combination with a highly efficient 'one-pot' cyclization-folding approach we obtained an RTD-1 based peptide that was around 10-times more active than wild type RTD-1 in inhibiting LF protease (IC50 = 43 ± 3 nM, Ki = ...

Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.

RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein we report our lead-optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis...

Identification of High-potency Human TLR8 and Dual TLR7/TLR8 Agonists in Pyrimidine-2,4-diamines.

The induction of Toll-like receptor 7 (TLR7)-dependent Type I interferons (IFN-α/β) from plasmacytoid dendritic cells as well as the production of TLR8-dependent Type II interferon (IFN-γ), TNF-α, and IL-12 in myeloid dendritic cells are of importance in generating T helper-1 biased adaptive immune responses. In an effort to identify novel dual TLR7/TLR8-active compounds, we undertook structure-activity relationship studies in pyrimidine 2,4-diamines, focusing on substituents at C5. Several analogues su...

Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry.

G protein-coupled receptors (GPCRs) belong to a large superfamily of membrane receptors mediating a variety of physiological functions. As such they are attractive targets for drug therapy. However, it remains a challenge to develop subtype selective GPCR ligands, due to the high conservation of orthosteric binding sites. Bitopic ligands have been employed to address the selectivity problem by combining (linking) an orthosteric ligand with an allosteric modulator, theoretically leading to high-affinity subt...

Discovery of 2-((3-acrylamido-4-methylphenyl)amino)-N-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chromosome (BMX) Kinase Inhibitor.

BMX is a member of TEC family non-receptor tyrosine kinase and is involved in a variety of critical physiological and pathological processes. Through combination of irreversible inhibitor design and type II inhibitor design approaches, we have discovered a highly selective and potent type II irreversible BMX kinase inhibitor compound 41 (CHMFL-BMX-078), which exhibited an IC50 of 11 nM by formation of a covalent bond with cysteine 496 residue in the DFG-out inactive conformation of BMX. It displayed a high ...

Thienopyrimidinone based sirtuin-2 (SIRT2)-selective inhibitors bind in the ligand induced 'selectivity pocket'.

Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have b...

Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase.

G9a-like protein (GLP) and G9a are highly homologous protein lysine methyltransferases (PKMTs) sharing approximately 80% sequence identity in their catalytic domains. GLP and G9a form a heterodimer complex and catalyze mono- and dimethylation of histone H3 lysine 9 and non-histone substrates. Although they are closely related, GLP and G9a possess distinct physiological and pathophysiological functions. Thus, GLP or G9a selective small-molecule inhibitors are useful tools to dissect their distinct biological...


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