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11:31 EST 2nd March 2015 | BioPortfolio

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Showing PubMed Articles 1–25 of 1,900+ from Journal of medicinal chemistry


Fighting Malaria: Structure-Guided Discovery of Nonpeptidomimetic Plasmepsin Inhibitors.

Plasmepsins are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting amino-acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Over the past decade, tremendous progress was made in the development of plasmepsin inhibitors using two strategies: structure-based drug design (SBDD) and structure-based virtual screening (SBVS). Herein, we review the inhibitors of Plms I-IV d...

Monday 18th November 1179

Structure Enabled Design of BAZ2-ICR, A Chemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B.

The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 (BAZ2-ICR) of the BAZ2A/B bromodomains through rapid optimization of a weakly potent starting point. A key feature of the presented inhibitors is an intramolecular aromatic stacking interaction that efficiently occupies the shallow bromodomain pockets. 13 represents an excellent chemical probe ...

Tuesday 21st May 1179

Correction to Tetra-Substituted Pyridinylimidazoles As Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase 3 for Potential Treatment of Neurodegenerative Diseases.

Sunday 20th January 1179

The Hippo Pathway and YAP/TAZ-TEAD Protein-Protein Interaction as Targets for Regenerative Medicine and Cancer Treatment.

The Hippo pathway is an important organ size control signaling network and the major regulatory mechanism of cell-contact inhibition. Yes Associated Protein (YAP) and Transcriptional co-Activator with PDZ-binding motif (TAZ) are its targets and terminal effectors: inhibition of the pathway promotes YAP/TAZ translocation to the nucleus, where they interact with Transcriptional Enhancer Associate Domain (TEAD) transcription factors and co-activate the expression of target genes, promoting cell proliferation. ...

Sunday 27th August 1177

Learning from PAINful lessons.

Chemical probes are important both as tools to understand biology and as starting points for drug leads, but not every active molecule makes a good probe; many react nonspecifically with thiols. These promiscuous inhibitors are worse than useless because they can mislead researchers and muddy the literature. Understanding the mechanisms of such compounds can prevent scientists from following false hits down blind alleys.

Tuesday 4th April 1177

Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes.

Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 Å2, and low permeability on Caco-2 cells, exhibited satisfactory poten...


Discovery of imidazo2,1-bthiazole HCV NS4B inhibitors exhibiting synergistic effect with other direct-acting antiviral agents.

The design, synthesis and SARs studies of novel inhibitors of HCV NS4B which based on imidazo[2,1-b]thiazole scaffold were described. Optimization of potency with respect to genotype 1b resulted in the discovery of two potent leads 26f (EC50=16 nM) and 28g (EC50= 31 nM). The resistance profile studies revealed that 26f and 28g targeted at HCV NS4B, more precisely the second amphipathic α helix of NS4B (4BAH2). Cross-resistance between our 4BAH2 inhibitors and other direct-acting antiviral agents targeting ...


2-Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as Potent Dissociated Glucocorticoid Receptor Agonists‡

A significant improvement in agonist activity of the previously described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated, glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy assay measuring repression of IL-1 induced MMP-13 expression was 3.5 nM, exhibiting 87% the maximal effect of dexamethasone (dex). It displayed a dissociated profile by exhibiting 42% of the max...


Development of a novel class of tubulin inhibitor from desmosdumotin B with a hydroxylated bicyclic B-ring.

A series of newly synthesized hydroxylated analogues of triethyldesmosdumotin B (TEDB) with a bicyclic B-ring exhibited a significantly different mode of action for affecting microtubule dynamics and spindle formation but had the same antiproliferative activity spectrum, including multidrug-resistant tumors.  These analogues efficiently induced cell cycle arrest at prometaphase and caused formation of immature multipolar spindles. 6'-Hydroxyl TEDB-TB (8) disrupted bipolar spindle formation but had a negli...

Wednesday 16th September 1175

Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design.

The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired ADME properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related Cathepsin D or negatively impacting brain penetration and ADME alignment, as e...

Saturday 13th June 1175

The discovery of macrocyclic XIAP antagonists from a DNA-programmed chemistry library, and their optimization to give lead compounds with in vivo antitumor activity.

Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray co-crystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.

Sunday 8th March 1175

Identification of Novel Aldose Reductase Inhibitors Based on Carboxymethylated Mercapto-Triazino-Indole Scaffold.

Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (13) was the most promising inhibitor, with an IC50 in submicromolar range and high selectivity, relative to aldehyde reductase. Crystal structure of aldose reductase complexed with 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excelle...


Quantum Chemistry Calculation-Aided Structural Optimization of Combretastatin A-4-like Tubulin Polymerization Inhibitors: Improved Stability and Biological Activity.

A potent combretastatin A-4 (CA-4) like tubulin polymerization inhibitor 22b was found with strong anti-tumor activity previously. However, they easily undergo cis-trans isomerization under natural light, and the resulting decrease in activity limits its further applications. In this study, we used quantum chemistry calculations to explore the molecular basis of its instability. Aided by the calculations, two round of structural optimization of 22b were conducted. Accelerated quantitative light stability te...


The strong antibacterial properties of anion transporters: a result of depolarization and weakening of the bacterial membrane.

The development of low molecular weight anionophores is an emerging topic in chemistry as the need for these compounds increases with the continuous discovery of pathologies involving anomalies in anion transport processes. Development of new concepts to initiate anion imbalance in living cells while fighting multidrug-resistant bacteria is a paramount topic. In this study, three series of benzimidazolium salts displaying high antimicrobial activity and low toxicity against human cells were designed, synthe...

Thursday 3rd October 1173

Exploitation of the Ability of γ-Tocopherol to Facilitate Membrane Co-localization of Akt and PHLPP1 to Develop PHLPP1-Targeted Akt Inhibitors.

Previously, we reported that Akt inactivation by γ-tocopherol (2) in PTEN-negative prostate cancer cells resulted from its unique ability to facilitate membrane co-localization of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase isoform 1), a Ser473-specific Akt phosphatase, through plekstrin homology (PH) domain binding. This finding provided a basis for exploiting 2 to develop a novel class of PHLPP1-targeted Akt inhibitors. Here, we used 3 (γ-VE5), a side chain-truncated 2 derivative, ...

Thursday 12th July 1172

Discovery and safety profiling of a potent pre-clinical candidate, (4-4-(3R)-3-(hydroxycarbamoyl)-8-azaspiro4.5decan-3-ylsulfonylphenoxy-N-methyl-benzamide) (CM-352), for the prevention and treatment of hemorrhage.

Discovery of potent and safe therapeutics that improve upon currently available antifibrinolytics; e.g., tranexamic acid (TXA, 1) and aprotinin, has been challenging. Matrix metalloproteinases (MMP) participate in thrombus dissolution; then, we designed a novel series of optimized MMP inhibitors that went through phenotypic screening consisting of thromboelastometry and mouse tail-bleeding. Our optimized lead compound, CM-352 (2), inhibited fibrinolysis in human whole blood functional assays and was more ef...

Saturday 3rd March 1172

Design, synthesis and biological evaluation of novel matrix metalloproteinase inhibitors as potent antihemorrhagic agents: from hit identification to an optimized lead.

Growing evidence suggests that matrix metalloproteinases (MMP) are involved in thrombus dissolution; then, considering that new therapeutic strategies are required for controlling hemorrhage, we hypothesized that MMP inhibition may reduce bleeding by delaying fibrinolysis. Thus, we designed and synthesized a novel series of MMP inhibitors to identify potential candidates for acute treatment of bleeding. Structure-based and knowledge-based strategies were utilized to design this novel chemical series, α-spi...


Stem Cell Mobilizers Targeting Chemokine Receptor CXCR4 : Renoprotective Application in Acute Kidney Injury.

We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4+ cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke and cancer metastasis. More importantl...


A binding mode hypothesis of tiagabine confirms liothyronine effect on γ-aminobutyric acid transporter 1 (GAT1).

Elevating GABA levels in the synaptic cleft by inhibiting its reuptake carrier GAT1 is an established approach for the treatment of CNS disorders like epilepsy. With the increasing availability of crystal structures of transmembrane transporters, also structure-based approaches to elucidate the molecular basis of ligand-transporter interaction become feasible. Experimental data guided docking of derivatives of the GAT1 inhibitor tiagabine into a protein homology model of GAT1 allowed to derive a common bind...

Saturday 20th June 1169

Discovery of Potent, Orally Bioavailable, Small-Molecule Inhibitors of WNT Signaling from a Cell-Based Pathway Screen.

WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognis...


Synthesis of CDDO-Amino Acid-Nitric Oxide Donor Trihybrids as Potential Antitumor Agents against Both Drug-sensitive and Drug-resistant Colon Cancer.

Seventeen CDDO-amino acid-NO donor trihybrids (4a-q) were designed and synthesized. Biological evaluation indicated that the most active compound 4c produced high levels of NO and inhibited the proliferation of drug-sensitive (HCT-8, IC50 = 0.294 μM) and drug-resistant (HCT-8/5-FU, IC50 = 0.232 μM) colon cancer cells, which were attenuated by an NO scavenger or typical substrate of PepT1. Furthermore, 4c triggered HCT-8 and HCT-8/5-FU cell apoptosis more strongly than CDDO-Me, inhibited the HIF-1α, Stat3...


Synthesis, SAR, and Series Evolution of Novel Oxadiazole-Containing 5-Lipoxygenase Activating Protein Inhibitors: Discovery of 2-4-(3-{(R)-1-4-(2-Amino-pyrimidin-5-yl)-phenyl-1-cyclopropyl-ethyl}-1,2,4oxadiazol-5-yl)-pyrazol-1-yl-N,N-dimethyl-acetamide (BI 665915).

The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of ...

Tuesday 20th November 1167

Activity of 2-Aryl-2-(3-indolyl)acetohydroxamates Against Drug-Resistant Cancer Cells.

Many types of tumor, including glioma, melanoma, non-small cell lung, esophageal, head and neck cancer, among others, are intrinsically resistant to apoptosis induction and poorly responsive to current therapies with proapoptotic agents. In addition, tumors often develop multi-drug resistance based on the cellular efflux of chemotherapeutic agents. Thus, novel anticancer agents capable of overcoming these intrinsic or developed tumor resistance mechanisms are urgently needed. We describe a series of 2-aryl-...

Tuesday 26th June 1167

A selective, non-toxic CB2 cannabinoid o-quinone with in vivo activity against triple negative breast cancer.

Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by high aggressiveness. There is no current targeted therapy for these patients whose prognosis, as a group, is very poor. Here, we report the synthesis and evaluation of a potent antitumor agent in vivo for this type of breast cancer designed as a combination of quinone/cannabinoid pharmacophores. This new compound (10) has been selected from a series of chromenopyrazolediones with full selectivity for the non-psychotr...

Monday 14th May 1167

Tau PET Imaging: Past, Present and Future.

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population. The good correlation of the density and neocortical spread of Neurofibrillary tangles (NFTs) with clinical AD disease progression offers an opportunity for the early diagnosis and staging using a non-invasive imaging technique such as Positron Emission Tomography (PET). Thus, PET imaging of NFTs holds promise not just as a diagnostic tool, but it may also enable the developmen...

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