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PubMed Journal Database | Journal of medicinal chemistry RSS

21:07 EST 24th November 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 1,200+ from Journal of medicinal chemistry

Discovery of Small-Molecule Inhibitors of Ubiquitin Specific Protease 7 (USP7) Using Integrated NMR and In-Silico Techniques.

USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53 and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical and computational approaches that led to the identification of 4-(2-aminopyridin-3-yl)-phenol compounds described by Kategaya et al.1 as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemica...

Discovery of an Orally Bioavailable Benzofuran Analogue that Serves as a β-amyloid Aggregation Inhibitor for the Potential Treatment of Alzheimer's Disease.

We developed an orally active and blood-brain barrier-permeable benzofuran analogue (8, MDR-1339) with potent anti-aggregation activity. Compound 8 restored cellular viability from Aβ-induced cytotoxicity but also improved the learning and memory function of AD model mice by reducing the Aβ aggregates in the brains. Given the high bioavailability and brain permeability demonstrated in our pharmacokinetic studies, compound 8 will provide a novel scaffold for an Aβ-aggregation inhibitor that may offer an a...

Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach.

A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with a biochemical and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity towards other Poly(ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in-vitro ADME profile as well as good oral bioavailability in mice, rats and dogs. Critical fo...

A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors.

The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we reported the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region, and then building into the LPF shelf. Herein we report the "hybridization" of a variety of KAc-binding fragments with a tetrahydroquinoline scaffold that makes optimal interactions with the LPF shelf, imparting enhanced potency and selectivity to the hybridized ligand. To de...

Allosteric inhibitors of SHP2 with therapeutic potential for cancer treatment.

SHP2, a cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene, is involved in multiple cell signaling processes including Ras/MAPK and Hippo/YAP pathways. SHP2 has been shown to contribute to the progression of a number of cancer types including leukemia, gastric and breast cancer. It also regulates T-cell activation by interacting with inhibitory immune checkpoint receptors such as the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA). Thus, SHP2 inhibitors have drawn g...

Semisynthesis and Biological Evaluation of Xanthone Amphiphilics as Selective, Highly Potent Antifungal Agents to Combat Fungal Resistance.

New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangostin resulted in interesting antifungal agents with a novel mode of action. Two lead compounds (1 and 2) showed potent antifungal activity against a wide range of fungal pathogens, including d...

Small Molecule Mitochondrial Uncouplers and Their Therapeutic Potential.

Small molecule mitohondrial uncouplers transport protons from the mitochondrial inner membrane space into the mitochondrial matrix independent of ATP synthase, uncoupling nutrient metabolism from ATP generation. The therapeutic potential of mitochondrial uncouplers have been investigated for the treatment metabolic diseases such as obesity and type 2 diabetes (T2D), as well as for neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. This perspective will review the mitochondrial...

The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious JAK1 Selective Inhibitor with Favorable Pharmacokinetic Properties.

The discovery of a potent selective low dose JAK1 inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical propert...

Discovery of Tropifexor (LJN452), a Highly Potent Non-Bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH).

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and non-alcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonis...

Design of Novel 3-Pyrimidinylazaindole based CDK2/9 Inhibitors with Potent In-vitro and In-vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model.

In the present study, novel series of 3-pyrimidinylazaindoles were designed and synthesized using bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in cell-cycle control and regulation of cell transcription. The present approach has given new dimensions to existing SAR and opens the new opportunity for lead optimization from comparatively inexpensive starting materials. The study led to the identification of alternative lead candidate 4ab with nanomolar ...

Protac-induced Protein Degradation in Drug Discovery: Breaking the Rules - or Just Making New Ones?

Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degradation concepts, and their resultin...

Chemical modification for proteolytic stabilization of the selective αvβ3 integrin RGDechi peptide: in vitro and in vivo activities on malignant melanoma cells.

Herein we report the synthesis and biological characterization of the novel peptide ψRGDechi as the first step towards novel targeted theranostics in melanoma. This pseudo-peptide is designed from our previously reported RGDechi peptide, known to bind selectively αvβ3 integrin, and differs for a modified amide bond at the main protease cleavage site. This chemical modification drastically reduces the enzymatic degradation in serum, compared to its parental peptide, resulting in an overall magnification o...

On the Importance of Rigidity in Designing Small Molecule Drugs to Tackle Protein-Protein Interactions (PPIs) through Stabilisation of Desired Confomers.

Tackling PPIs, particularly by stabilising clinically favoured conformations of target proteins, with orally available, bona fide small molecules remains a significant, but immensely worthwhile, challenge for the pharmaceutical industry. Success may be more likely through the application of nature's learnings to build intrinsic rigidity into the design of clinical candidates.

Tyrocidine A Analogues Bearing the Planar D-Phe-2-Abz Turn Motif: How Conformation Impacts Bioactivity.

The D-Phe-Pro β-turn of the cyclic β-hairpin antimicrobial decapeptide Tyrocidine A, (Tyrc A) was substituted with the D-Phe-2-aminobenzoic acid (2-Abz) motif in a synthetic analogue (1). NMR structure of 1 demonstrated that compound 1 retained the β-hairpin structure of Tyrc A with additional planarity, resulting in approx. 30-fold reduced haemolysis than Tyrc A. Although antibacterial activity was partially compromised, a single Gln to Lys substitution (2) restored activity equivalent to Tyrc A against...

RNA G-quadruplexes in Kirsten ras (KRAS) oncogene as targets for small molecules inhibiting translation.

The human KRAS transcript contains a G-rich 5'-UTR sequence (77 % GC) harbouring several G4 motifs capable to form stable RNA G-quadruplex (RG4) structures that can serve as targets for small molecules. A biotin-streptavidin pull-down assay showed that 4,11-bis(2-aminoethylamino)anthra[2,3-b]furan-5,10-dione (2a) binds to RG4s in the KRAS transcript under low-abundance cellular conditions. Dual-luciferase assays demonstrated that 2a and its analogue 4,11-bis(2-aminoethylamino)anthra[2,3-b]thiophene-5,10-dio...

Recent progress of small-molecule epidermal growth factor receptor (EGFR) inhibitors against C797S resistance in non-small-cell lung cancer.

The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein797 to serine790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current...

Novel linear lipopeptide paenipeptins with potential for eradicating biofilms and sensitizing Gram-negative bacteria to rifampicin and clarithromycin.

We report the structure-activity relationship (SAR) analyses of 17 linear lipopeptide paenipeptin analogues. Analogues 7, 12 and 17 were more potent than the lead compound. Analogue 17 was active against carbapenem-resistant and polymyxin-resistant pathogens. This compound at 40 μg/mL resulted in 3 log and 2.6 log reductions of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, respectively, in catheter-associated biofilms in vitro. Analogue 17 showed little hemolysis at 32 µg/ml and ...

Design, synthesis and biological assessment of biased allosteric modulation of the urotensin II receptor using achiral 1,3,4-benzotriazepin-2-one turn mimics.

Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip(4)]URP), which modulates the urotensin II receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization and ring closure. Several...

Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors.

N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trpanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stage 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a start point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.

Highly Selective Dopamine D3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores.

A series of potent and selective D3 receptor (D3R) analogues with diazaspiro alkane cores were synthesized. Radioligand binding of compounds 11, 14, 15a, and 15c revealed favorable D3R affinity (Ki = 12-25.6 nM) and were highly selective for D3R vs D3R (ranging from 264-905-fold). Variation of these novel ligand architectures can be achieved using our previously reported 10-20 minute benchtop C-N cross-coupling methodology, affording a broad range of arylated diazaspiro pre-cursors.

A Positive Allosteric Modulator of the Serotonin 5-HT2C Receptor for Obesity.

The 5-HT2CR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HT2CR allosteric modulators as safer anti-obesity drugs, a chemical library from Vivia Biotech was screened using ExviTech® platform. Structural modifications of identified hit VA240 in synthesized analogues 6-41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of ...

Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.

We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as clinical candidate.

X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors.

Excessive activity of striatal-enriched protein tyrosine phosphatase (STEP) in the brain has been detected in numerous neuropsychiatric disorders including Alzheimer's disease. Notably, knockdown of STEP in an Alzheimer mouse model effected an increase in the phosphorylation levels of downstream STEP substrates and a significant reversal in the observed cognitive and memory deficits. These data point to the promising potential of STEP as a target for drug discovery in Alzheimer's treatment. We previously re...

Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Non-Cleavable Drug-Linkers.

Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7) or piperazine (8) link to the PBD. In vitro IC50s were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 µg/mL (7 inactive...

N-Butyl-L-Deoxynojirimycin (L-NBDNJ): Synthesis of an Allosteric Enhancer of α-Glucosidase Activity for the Treatment of Pompe Disease.

The highly stereocontrolled de novo synthesis of L-NBDNJ (the unnatural enantiomer of the iminosugar drug Miglustat) and a preliminary evaluation of its chaperoning potential are herein reported. L-NBDNJ is able to enhance lysosomal α-glucosidase levels in Pompe disease fibroblasts, either when administered singularly or when co-incubated with the recombinant human α-glucosidase. In addition, differently from its D-enantiomer, L-NBDNJ does not act as a glycosidase inhibitor.


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