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20:24 EDT 1st October 2014 | BioPortfolio

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Showing PubMed Articles 1–25 of 1,800+ from Journal of medicinal chemistry

Monday 26th November 1082

Trehalose- and glucose-derived glycoamphiphiles: small-molecule and nanoparticle Toll-like Receptor 4 (TLR4) modulators.

An increasing number of pathologies have been linked to Toll-like Receptor 4 (TLR4) activation and signaling. New hit and lead compounds that target the TLR4 activation process are urgently needed. We report on the synthesis and biological properties of protonatable glycolipids based on glucose and trehalose scaffolds. Some of these compounds potently inhibit TLR4 activation and signaling in cells transfected with human and mouse variants of TLR4, MD-2 and CD14 receptors and are active in inhibiting TLR4-de...

Thursday 16th August 1082

Crystallographic and Receptor Binding Characterization of Plasmodium falciparum Macrophage Migration Inhibitory Factor Complexed to Two Potent Inhibitors.

We report the crystal structures of two inhibitors of Plasmodium falciparum macrophage migration inhibitory factor (PfMIF) with nanomolar Ki's, analyze their interactions with the active site of PfMIF, and provide explanations regarding their selectivity of PfMIF versus human MIF. These inhibitors were also found to selectively inhibit interactions between PfMIF and the human MIF receptor CD74. The results of this study provide the framework for the development of new therapeutics that target PfMIF.

Friday 27th April 1082

How a β-D-Glucoside Side Chain Enhances Binding Affinity to Thrombin of Inhibitors Bearing 2-Chlorothiophene as P1 Moiety: Crystallography, Fragment Deconstruction Study and Evaluation of Antithrombotic Properties.

The β-D-glucose-containing compound 3, bearing 2-chlorothiophene and 1-isopropylpiperidine moieties as binders of the S1 and S4 pockets, respectively, proved to be potent competitive inhibitor of factor Xa (fXa, Ki = 0.090 nM) and thrombin (fIIa, Ki = 100 nM). The potency of 3 increases, over the parent compound 1, against fIIa (110-fold) much more than against fXa (7-fold). Experimental deconstruction of 3 into smaller fragments revealed a binding cooperativity of the P3/P4 and C3-alkyl-linked -D-gluco...

Wednesday 17th January 1082

Oligo-beta-(1→3)-glucans: Impact of thio-bridges on immunostimulating activities and the development of cancer stem cells.

Recent developments of innovative anti-cancer therapies are based on compounds likely to stimulate the immune defense of the patients. beta-(1→3)-Glucans are natural polysaccharides well known for their immunostimulating properties. We report here on the synthesis of small oligo-beta-(1→3)-glucans characterized by thioglycosidic linkages. The presence of sulfur atom(s) was not only crucial to prolong in vivo immunoactive activities in time, compared to native polysaccharides, but has also a direct impac...


Non-Peptide Small Molecule Agonist and Antagonists Original Leads for Neuropeptide FF1 and FF2 Receptors.

Neuropeptide FF1 and FF2 receptors (NPFF1-R and NPFF2-R), and their endogenous ligand NPFF, are one of only several systems responsible for mediating opioid-induced hyperalgesia, tolerance and dependence. Currently, no small molecules displaying good affinity or selectivity for either subtype have been reported, to decipher the role of NPFF2-R as it relates to opioid-mediated analgesia, for further exploration of NPFF1-R, or for medication development for either subtype. We report the first non-peptide smal...


Modulation of cAMP specific PDE without emetogenic activity: new sulfide-like PDE7 inhibitors.

A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson's disease (PD) treatment. By analysis of the cell protection produced by some small molecules, a diphenyl sulfide compound was revealed to be a new phosphodiesterase 7 (PDE7) inhibitor and identified as a new hit. This result allows us to confirm the utility of PDE7 inhibitors as a potential pharmacological treatment of PD. Based on these data, a diverse family of diphenyl sulfides has been developed an...


Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1' Pocket in the Design of Selective, Small Molecule Inhibitors.

Matrix metalloproteinases (MMPs) are important targets for pathological conditions such as arthritis, chronic obstructive pulmonary disease and cancer. The failure of the first broad-spectrum MMP inhibitors in clinical trials has led researchers to address the selectivity as one of their main objectives. The S1' pocket has been widely used to modulate the selectivity of these enzymes because it displays the highest variability in length and shape among MMPs. In this perspective, we encourage medicinal chemi...


Design, synthesis, structure function relationship, bioconversion and pharmacokinetic evaluation of ertapenem prodrugs.

Abstract Described here are synthesis and biological evaluations of diversified groups of over fifty seven ertapenem prodrugs which include alkyl, methylenedioxy, carbonate, cyclic carbonate, carbamate esters, and esters containing active transport groups (e.g., carboxyl, amino acid, fatty acids, cholesterol) and macrocyclic lactones linking the two carboxyl groups. Many of the prodrugs were rapidly hydrolyzed in rat plasma but not in human plasma and were stable in simulated gastrointestinal fluid. The die...


Potent Cholesteryl Ester Transfer Protein Inhibitors of Reduced Lipophilicity: 1,1'-Spiro-Substituted Hexahydro-furoquinoline Derivatives.

A series of 1,1'-spiro-substituted hexahydrofuroquinoline derivatives exhibiting potent CETP inhibition at reduced lipophilicity was identified. A focused SAR exploration led to the potent and comparatively polar CETP inhibitor 26 showing robust HDL-C elevation and LDL-C reduction in transgenic hCETP/hApoB-100 mice. Compound 26 was also shown to positively differentiate from highly lipophilic CETP inhibitors in its complete elimination from fat tissue in hCETP transgenic mice as evident within 21 days after...

Thursday 5th November 1079

Structural basis for inhibition of mycobacterial and human adenosine kinase by 7-substituted 7-(het)aryl-7-deazaadenine ribonucleosides.

Adenosine kinase (ADK) from Mycobacterium tuberculosis (Mtb) was selected as a target for design of antimycobacterial nucleosides. Screening of 7-(het)aryl-7-deazaadenine ribonucleosides with Mtb and human (h) ADKs and testing with wild-type and drug-resistant Mtb strains identified specific inhibitors of Mtb ADK with micromolar antimycobacterial activity and low cytotoxicity. X-ray structures of complexes of Mtb and hADKs with 7-ethynyl-7-deazaadenosine showed differences in inhibitor interactions in the a...

Wednesday 29th July 1079

Multitarget drug design strategy: quinone-tacrine hybrids designed to block amyloid-beta aggregation and to exert anticholinesterase and antioxidant effects.

We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 12-29 displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-β (Aβ) aggregation. The X-ray analysis of AChE-20 complex allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Selected compounds 16 and 20 showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and pri...

Tuesday 3rd March 1079

Potent Heterocyclic Ligands for Human Complement C3a Receptor.

The G protein coupled receptor (C3aR) for human inflammatory protein complement C3a is an important component of immunity, inflammatory and metabolic disease. A flexible compound (N2-[(2,2-diphenylethoxy)acetyl]-L-arginine, 4), known as a weak C3aR antagonist (IC50 µM), was transformed here into potent agonists (EC50 nM) of human macrophages (Ca(2+) release in HMDM) by incorporating aromatic heterocycles. Antagonists were also identified. A linear correlation between binding affinity for C3aR and calculate...


Binding modes of reverse fosmidomycin analogs towards the antimalarial target IspC.

1-Deoxy-D-xylulose 5-phosphate reductoisomerase of Plasmodium falciparum (PfIspC), believed to be the rate-limiting enzyme of the non-mevalonate pathway of isoprenoid biosynthesis (MEP pathway), is a clinically validated antimalarial target. The enzyme is efficiently inhibited by the natural product fosmidomycin. In order to gain new insights into the structure activity relationships of reverse fosmidomycin analogs, several reverse analogs of fosmidomycin were synthesized and biologically evaluated. The 4-m...


Discovery of 2-5-(4-Fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanylmethyl-phenylboronic acid (SX-517): A Non-Competitive Boronic Acid Antagonist of CXCR1 and CXCR2.

The G protein-coupled chemokine receptors CXCR1 and CXCR2 play key roles in inflammatory diseases and carcinogenesis. In inflammation, they activate and recruit polymorphonuclear cells (PMNs) through binding of the chemokines CXCL1 (CXCR1) and CXCL8 (CXCR1 and CXCR2). Structure-activity studies that examined the effect of a novel series of S-substituted 6-mercapto-N-phenyl-nicotinamides on CXCL1-stimulated Ca2+ flux in whole human PMNs led to the discovery of 2-[5-(4-Fluoro-phenylcarbamoyl)-pyridin-2-ylsulf...

Thursday 28th August 1078

Optimized Protein Kinase C θ (PKCθ) Inhibitors Reveal Only Modest Anti-Inflammatory Efficacy in a Rodent Model of Arthritis.

We previously demonstrated that selective inhibition of Protein Kinase C θ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1, 2 However, a high concentration was required for efficacy thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimizing potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures resulti...

Friday 13th June 1078

Extending the Structure-Activity Relationship of Anthranilic Acid Derivatives As Farnesoid X Receptor Modulators: Development of a Highly Potent Partial Farnesoid X Receptor Agonist.

The ligand activated transcription factor nuclear farnesoid X receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the receptor ...

Tuesday 20th May 1078

Beyond C, H, O and N! Analysis of the Elemental Composition of US FDA Approved Drug Architectures.

The diversity of elements among US FDA approved pharmaceuticals is analyzed and reported, with a focus on atoms other than carbon, hydrogen, oxygen and nitrogen. Our analysis reveals that sulfur, chlorine, fluorine and phosphorous represent about 90% of elemental substitutions, with sulfur being the 5th most used element followed closely by chlorine, then fluorine and finally phosphorous in the 8th place. The remaining ten percent of substitutions are represented by 16 other elements of which bromine, iodin...

Wednesday 1st January 1078

Analysis of the Structural Diversity, Substitution Patterns and Frequency of Nitrogen Heterocycles among US FDA Approved Pharmaceuticals.

Nitrogen heterocycles are among the most significant structural components of pharmaceuticals. Analysis of our database of US FDA approved drugs reveals that 59% of unique small molecule drugs contain a nitrogen heterocycle. In this perspective we report on the top 25 most commonly utilized nitrogen heterocycles found in pharmaceuticals. The main part of our analysis is divided into seven sections: 3 & 4, 5, 6 and 7 & 8-membered, as well as fused, bridged bicyclic and macrocyclic nitrogen heterocycles. Each...


Discovery and Characterization of MAPK-activated Protein Kinase-2 Prevention of Activation Inhibitors.

Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary SAR studies revealed substructural features which influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, SPR, 2D protein NMR and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds ...


Discovery of N-substituted Oseltamivir Derivatives as Potent and Selective Inhibitors of H5N1 Influenza Neuraminidase.

To discover Group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound 20l was the most potent N1-selective inhibitor, with IC50 values of 0.0019 µM, 0.0038 µM and 0.0067 µM against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound 32 was another potent N1-selective inhibitor that exhibited a...

Friday 5th October 1076

Development of Novel Neurokinin 3 Receptor (NK3R) Selective Agonists with Resistance to Proteolytic Degradation.

Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the neurokinin-3 receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. Based on degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity.

Tuesday 17th July 1076

Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands.

Nuclear and G-protein coupled receptors are considered major targets for drug discovery. FXR and GP-BAR1, two bile acid-activated receptors, have gained increasing consideration as druggable receptors. Because endogenous bile acids often target both receptor families, the development of selective ligands has been proven difficult exposing patients to side-effects linked to an unwanted activation of one of the two receptors. In the present study we describe a novel library of semi-synthetic bile acid derivat...

Monday 21st March 1075

Development of a Novel Class of Mitochondrial Ubiquinol-Cytochrome c Reductase Binding Protein (UQCRB) Modulators as Promising Antiangiogenic Leads.

Recently, we identified a novel therapeutic target and a small molecule for regulating angiogenesis. Our study showed that ubiquinol-cytochrome c reductase binding protein (UQCRB) of the mitochondrial complex III plays a crucial role in hypoxia-induced angiogenesis via mitochondrial reactive oxygen species (ROS) mediated signaling. Herein, we developed new synthetic small molecules that specifically bind to UQCRB and regulate its function. To improve the pharmacological properties of 6-((1-hydroxynaphthalen...


Development of (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336: novel 2-amidinophenylbenzamides as potent inhibitors of Venezuelan Equine Encephalitis Virus.

Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC50 = 0.8 μM), limited cytotoxic liability (CC50 > 50 μM), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 μM). Scaffold optimization rev...

Sunday 27th June 1074

ST7612AA1, a thioacetate-ω (γ-lactam carboxamide) derivative selected from a novel generation of oral HDAC inhibitors.

A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the omega position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC i...

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