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PubMed Journal Database | Journal of medicinal chemistry RSS

20:43 EDT 23rd April 2014 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage 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 1,600+ from Journal of medicinal chemistry


Foundation-directed therapeutic development in Huntington's disease.

ABSTRACT. Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that devastates patients and their families. It is caused by expansion of the CAG repeat in the huntingtin gene (HTT) and characterized pathologically by the loss of pyramidal neurons in several cortical areas, striatal medium spiny neurons, and hypothalamic neurons. Clinically, a distinguishing feature of the disease is uncontrolled involuntary movements (chorea) accompanied by progressive cognitive and psychiatric impai...


Back pocket flexibility provides group-II PAK selectivity for type 1½ kinase inhibitors.

Structure based methods were used to design a potent and highly selective group-II PAK inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group-II PAKs approached by these type 1½ binders was found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group-I-PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented. A concentra...


The design of potent and selective inhibitors to overcome clinical ALK mutations resistant to crizotinib.

Crizotinib (1), an ALK receptor tyrosine kinase inhibitor approved by the FDA in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e which was potent across a broad panel of engineered ALK mutant cell lines, showed suitable pre-clinical PK and...


Discovery of Innovative Therapeutics: Today's Realities and Tomorrow's Vision. 2. Pharma Challenges and Their Commitment to Innovation.

The pharmaceutical industry is currently facing enormous challenges, including reduced efficiency, a stagnant success rate, patent expirations for key drugs, fierce price competition from generics, high regulatory hurdles and the industry's perceived tarnished image. There is a clear need for change in the paradigms designed to address these challenges. Pharma has responded by embarking on a range of initiatives. Other sectors have also responded. In the wake of much criticism, the National Institutes of He...


Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ-Secretase Modulators.

Herein we describe the design and synthesis of a novel series of γ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. In order to align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorab...


Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines.

A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity. The most potent inhibitors in this series contained a five-membered heterocycle at the 2-position of the benzimidazole, leading to highly potent and selective compounds that exploit the differences in the size of a binding pocket adjacent to the NADPH cofactor between the bacterial and human DHFR enzymes. Typical of these...


Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 2'-Fluoro-3'-(substituted pyridinyl)-7-deschloroepibatidine Analogues.

2'-Fluoro-3-(substituted pyridine)epibatidine analogues 7a-e and 8a-e were synthesized and their in vitro and in vivo nAChR properties determined. 2'-Fluoro-3'-(4"-pyridinyl)deschloroepibatidine (7a) and 2'-fluoro-3'-(3"-pyridinyl)deschloroepibatidine (8a) were synthesized as bioisosteres of the 4'-nitrophenyl lead compounds 5a and 5g. Comparison of the in vitro nAChR properties of 7a and 8a to those of 5a and 5g showed that 7a and 8a had in vitro nAChR properties similar to those of 5a and 5g, but both wer...


Switching invariant Natural Killer T (iNKT) Cells Response from Anticancerous to Anti-Inflammatory Effect: Molecular Bases.

Since the discovery in 1995 of α-galactosylceramide 1 (α-GalCer), also known as KRN70001, hundreds of compounds have been synthesized in order to activate invariant natural killer T (iNKT) cells. Such keen interest for this lymphocyte cell type is due to its ability to produce different cytokines that bias the immune response toward a Th1 or Th2 profile. Thus an understanding of the immune polarization mechanism via iNKT activation may pave the way toward new therapeutics in various domains including canc...


Evidence for two populated conformations for the dimeric LeX and LeALeX tumor associated carbohydrate antigens.

The conformational behavior of tumor associated carbohydrate antigens (TACAs) dimLex and LeaLex was studied using a combination of NMR experiments and molecular dynamic simulations. It is shown that within the hexasaccharides, the Lex and Lea branched trisaccharides fragments adopt the rigid "stacked" conformation known for the isolated trisaccharide antigens. In contrast, the β-D-GlcNAc-(1→3)-D-Gal glycosidic bond that connects the two Lex trisaccharides in dimLex, and the Lea trisaccharide to the Lex t...


Double-edged Swords as Cancer Therapeutics: Novel Orally Active Small Molecules Simultaneously Inhibit p53-MDM2 Interaction and the NF-κB Pathway.

Simultaneous inactivation of p53 and hyperactivation of nuclear factor-κB (NF-κB) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-κB. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-κB pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazol...


The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis.

Natural products are the major sources of currently available anticancer drugs. We recently reported that phenanthrene-based tylophorine derivative-1 (PBT-1) may be a potential antitumor agent for lung adenocarcinoma. We therefore examined the direct targets of PBT-1 and their effects in inhibiting lung adenocarcinoma. We found that PBT-1 reduced the level of Slug and inhibited the migration, invasion, and filopodia formation of lung adenocarcinoma CL1-5 cells in vitro. In addition, PBT-1 displayed in vivo...


Rapid Identification of Keap1-Nrf2 Small Molecule Inhibitors through Structure-Based Virtual Screening and Hit-Based Substructure Search.

In this study, rapid structure-based virtual screening and hit-based substructure search were utilized to identify small molecules that disrupt the interaction of Keap1-Nrf2. Special emphasis was placed toward maximizing the exploration of chemical diversity of the initial hits while economically establishing informative structure-activity relationship (SAR) of novel scaffolds. Moreover, our most potent non-covalent inhibitor exhibits three times improved cellular activation in Nrf2 activation than the most...


Synthesis and biological evaluation of novel tetrahydro-β-carboline derivatives as anti-tumor growth and metastasis agents through inhibiting the transforming growth factor-β signaling pathway.

The transforming growth factor beta (TGFβ) signaling cascade is considered as one of the pivotal oncogenic pathways in most advanced cancers. Inhibition of the TGFβ signaling pathway by specific antagonists, neutralizing antibodies or small molecules, is considered as an effective strategy for the treatment of tumor growth and metastasis. Here we demonstrated the identification of a series of tetrahydro-β-carboline derivatives which potentially inhibit the TGFβ signaling pathway from virtual screening....


Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases.

The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence the JAKs have received significant attention in recent years from the pharmaceutical and biotech industries as therapeutic targets. In this perspective we provide a review of the JAK pathways, the structure, function and activation of the JAK enzymes followed by a detailed look at th...


Discovery of 8-Cyclopentyl-2-4-(4-methyl-piperazin-1-yl)-phenylamino-7-oxo-7,8-dihydro-pyrido2,3-dpyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-related Kinase 5 (ARK5).

The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multi kinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure activity relationship trends that can...


Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept.

Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enz...


Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles.

In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK...


Polyamine Transport Inhibitors: Design, Synthesis, and Combination Therapies with Difluoromethylornithine.

The development of polyamine transport inhibitors (PTIs), in combination with the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), provides a method to target cancers with high polyamine requirements. The DFMO+PTI combination therapy results in sustained intracellular polyamine depletion and cell death. A series of substituted benzene derivatives were evaluated for their ability to inhibit the import of spermidine in DFMO-treated Chinese hamster ovary (CHO) and L3.6pl human pancreatic cancer...


Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa Inhibitors.

Antithrombotic agents which are inhibitors of Factor XIa (FXIa), have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound (1) was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in ani...


Mutagenesis Studies of the 14 Å Internal Cavity of Histone Deacetylase 1: Insights towards the Acetate Escape Hypothesis and Selective Inhibitor Design.

Histone deacetylase (HDAC) proteins are promising targets for cancer treatment, as shown by the approval of two HDAC inhibitors for treatment of cutaneous T-cell lymphoma. HDAC1 in particular has been linked to cell growth and cell cycle regulation and is therefore an attractive target for anti-cancer drugs. An HDAC1 homology model revealed that the active site contains a hydrophobic 11 Å active site channel, with a 14 Å internal cavity at the bottom of the active site. Several computational and biochemic...


Fragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT).

Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against h...


Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A.

We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogs. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values...


A novel class of benzoic acid ester derivatives as potent PDE4 inhibitors for inhaled administration in the treatment of respiratory diseases.

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored and structural...


Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase.

Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and memb...


Synthesis, cytostatic, antimicrobial and anti-HCV activity of 6-substituted 7-(het)aryl-7-deazapurine ribonucleosides.

A series of eighty 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl or oxo group at position 6 or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, was prepared and the biological activity of the compounds was studied and compared with that of the parent 7-(het)aryl-7-deazaadenosine series. Several of the compounds, in particular 6-substituted 7-deazapurine derivatives bearing a furyl or ethynyl group at...

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