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18:10 EDT 6th July 2015 | BioPortfolio

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Showing PubMed Articles 1–25 of 2,100+ from Journal of medicinal chemistry


New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity and Repression of Hedgehog-dependent Cancer.

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multidrug resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of He...

Sunday 20th December 1282

Structure-Based Development of a Protein-Protein Interaction Inhibitor Targeting Tumor Necrosis Factor Receptor-Associated Factor 6.

The interactions between tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF superfamily receptors (TNFRSFs) are promising targets for rheumatoid arthritis (RA) treatment. However, due to the challenging nature of protein-protein interactions (PPIs), a potent inhibitor that surpasses the affinity of the TRAF6-TNFRSF interactions has not been developed. We developed a small molecule PPI inhibitor of TRAF6-TNFRSF interactions using NMR and in silico techniques. The most potent compound, T...


Structure-affinity relationships (SARs) and structure-kinetics relationships (SKRs) of Kv11.1 blockers.

Kv11.1 (hERG) blockers with comparable potencies but different binding kinetics might display divergent pro-arrhythmic risks. In the present study, we explored structure-kinetics relationships in four series of Kv11.1 blockers next to their structure-affinity relationships. We learned that despite dramatic differences in affinities and association rates, there were hardly any variations in the dissociation rate constants of these molecules with residence times (RTs) of a few minutes only. Hence, we synthesi...


Correction to Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins.


Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β3-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side-Effects.

Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human β3-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant β3-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the α1A-AR (EC50 = 219 nM, selectivity:α1A/β3 = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the sele...

Monday 8th December 1281

Nucleoside Diphosphate Prodrugs: Non-symmetric DiPPro-Nucleotides.

Non-symmetric DiPPro-nucleotides are described as nucleoside diphosphate (NDP) delivery systems. The basic concept of this approach is to attach two different bis(acyloxybenzyl)-moieties at the -phosphate moiety of a nucleoside diphosphate. Two types of DiPPro-prodrugs were studied: DiPPro-compounds bearing two alkanoylbenzyl residues in which the length of the alkanoyl ester group differed and second, DiPPro-compounds bearing an alkanoylbenzyl and a benzoylbenzyl group as bioreversible prodrug moieties....

Wednesday 22nd January 1281

Discovery of CREBBP Bromodomain Inhibitors by High-throughput Docking and Hit Optimization Guided by Molecular Dynamics.

We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based virtual screening. First a library of about 100,000 molecular fragments was docked with evaluation of force field energy and desolvation penalty. Then the top ranking fragments were used for selecting molecules for flexible docking from a library of nearly two million compounds. Upon flexible docking and ranking, only 17 molecules from the two-million library were tested in vitro, and two of them showed an equilibrium dissocia...


DARC: mapping surface topography by ray-casting for effective virtual screening at protein interaction sites.

Protein-protein interactions represent an exciting and challenging target class for therapeutic intervention using small molecules. Protein interaction sites are often devoid of the deep surface pockets presented by "traditional" drug targets, and crystal structures reveal that inhibitors typically engage these sites using very shallow binding modes. As a consequence, modern virtual screening tools developed to identify inhibitors of traditional drug targets do not perform as well when they are instead depl...


N-Phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATP competitive DNA Gyrase B Inhibitors: Design, Synthesis, and Evaluation.

Bacterial DNA gyrase is a well-known and validated target in the design of antibacterial drugs. However, inhibitors of its ATP binding subunit, DNA gyrase B (GyrB), have so far not reached clinical use. In the present study, three different series of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides were designed and prepared as potential DNA gyrase B inhibitors. The IC50 values of compounds on DNA gyrase from Escherichia coli were in the low micromolar range, with the best compound, (4-(4,5-dibromo-...


Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase γ.

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.


Aurora Kinase Inhibition: A New Light in the Sky?

The quest for potent and selective small molecule inhibitors of the Aurora kinases has been long and resource intensive with multiple agents progressed to the clinic. To definitively explore the potential for clinical efficacy at well-tolerated dosing schedules requires a well-characterized, selective inhibitor with pharmacokinetic properties, flexible dosing regimen, and suite of target engagement biomarkers suitable for clinical use. AMG900 is a promising opportunity to definitively test the clinical bene...


Discovery and Modification of in vivo active Nrf2 Activators with 1, 2, 4-oxadiazole Core: Hits Identification and Structure-Activity Relationship Study.

Induction of phase II antioxidant enzymes by activation of Nrf2/ARE pathway has been recognized as a promising strategy for the regulation of oxidative stress-related diseases. Herein we report our effort on the discovery and optimization of Nrf2 activators with 1,2,4-oxadiazole core. Screening of in-house database containing 7500 compounds by ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecular similarity search by the combination o...


Structure-Based Design of Potent HIV-1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme-Inhibitor X-ray Structural Studies.

We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the S1 subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofu...

Thursday 26th September 1275

Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases.

The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared and tested as monoamine oxidases (MAOs), acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE and BChE, but low selectivity. More rigid inhibitors, ...

Sunday 9th December 1274

Biological Efficacy and Toxicity of Diamidines in Myotonic Dystrophy Type 1 Models.

Myotonic Dystrophy type 1 (DM1) is a disease that can be characterized by errors in alternative splicing. The causative agent of mis-splicing in DM1 is an inherited CTG repeat expansion located in the 3' UTR of the DMPK gene. When transcribed, CUG repeat expansion RNA sequesters an important family of alternative splicing regulators known as MBNL proteins. Sequestration of the MBNL proteins results in the mis-splicing of its regulated transcripts. Previous work has demonstrated that pentamidine, a bis-benza...


Discovery of 4,5,6,7-Tetrahydrobenzo1,2-dthiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site.

The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Growing resistance against fluoroquinolones, that also target these enzymes, limits their therapeutic potential and stimulates the search for novel inhibitor classes targeting their ATP-binding sites. Starting from a library of marine alkaloid oroidin analogs, we identified low micromolar inhibitors of E. coli DNA...


Therapeutic potential of 5-HT6 receptor agonists.

Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After two decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents - mainly antagonists - are currently undergoing clinical trial....


18F-labeled 1,4-Dioxa-8-azaspiro4.5decane Derivative: Synthesis and Biological Evaluation of a Sigma-1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent.

We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ1 receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (Ki = 5.4 ± 0.4 nM) for σ1 receptors and selectivity for σ2 receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [18F]5a was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of > 95%, and a specific ac...


The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridising fragment and HTS hits.

The hybridisation of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm), based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimisation of activity with maintenance of ligand efficiency, whilst the focus on physical properties delivered compounds with excellent pharmacokinetic exposure that enabled an ac...


Strategies for the Discovery of Target-specific or Isoform-selective Modulators.

Currently, the creation of class- and isoform-selective modulators of biologically important targets is a particularly challenging problem, because different isoforms within a protein family often show striking similarity in spatial quaternary structure, especially at the catalytic sites or binding pockets. Therefore, an understanding of both the precise three-dimensional structure of the target protein and the mechanisms of action of modulators is important for developing more effective and selective agent...


Novel Octahydropyrrolo3,4-cpyrroles are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate.

The pre-clinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats and this work ultimately led to the identification of a compound that progressed into human clinical trials fo...

Thursday 12th September 1269

Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase.

The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.

Wednesday 15th May 1269

Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery.

Tropical protozoal infections are a significant cause of morbidity and mortality world-wide; four, in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life-years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and non-toxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested thi...


Discovery of Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor CC-223.

We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of...

Thursday 13th October 1267

Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.

Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2...