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10:10 EDT 4th August 2015 | BioPortfolio

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

Saturday 29th July 1307

A novel covalent mTOR inhibitor, DHM25, shows in vivo anti-tumor activity against triple-negative breast cancer cells.

Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologs that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designate...

Thursday 27th April 1307

2-Phenoxy-1,4-naphthoquinones: from a multitarget antitrypanosomal to a potential antitumor profile.

A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the g...

Tuesday 6th April 1305

Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors.

ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.


New Frontiers in Druggability.

A powerful early approach to evaluating the druggability of proteins involved determining the hit rate in NMR-based screening of a library of small compounds. Here we show that a computational analog of this method, based on mapping proteins using small molecules as probes, can reliably reproduce druggability results from NMR-based screening, and can provide a more meaningful assessment in cases where the two approaches disagree. We apply the method to a large set of proteins. The results show that, because...


Discovery of VX-509 (Decernotinib): A Potent and Selective Janus kinase (JAK) 3 Inhibitor for the Treatment of Autoimmune Diseases.

While several therapeutic options exist, the need for more effective, safe and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, an...


A Ligand-Based Drug Design, Discovery of 4-Trifluoromethyl-7,8-Pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2.

In humans, cytochrome P450 1A2 is the major enzyme metabolizing environmental aryl amines or heterocyclic amines into carcinogens. Since evidence shows that planar triangle-shaped molecules are capable of selectively inhibiting P450 1A2, sixteen triangular flavone and coumarin derivatives were designed and synthesized for these studies. Among these compounds, 7,8-furanoflavone time-dependently inhibits P450 1A2 with a KI value of 0.44 µM. With a 5-min pre-incubation in the presence of NADPH, 0.01 µM of 7,...

Saturday 7th November 1304

Discovery of 2-1-(4,4-difluorocyclohexyl)piperidin-4-yl-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): a Potent, Orally Available and Highly Selective PARP-1 Inhibitor for Cancer Therapy.

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing. However all current compounds unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerv...

Sunday 12th July 1304

Carbamoyl triazoles, Known Serine Protease Inhibitors, are a potent New Class of Antimalarial.

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14 000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Follow up work by Calderon et al clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set we identified the carbamoyl triazole TCMDC-134379 (1), a known serine protease inhibitor, as an excellent start...


Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP.

Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis and pro-survival signaling pathways, whose deregulation is often associated with tumor genesis and tumor growth. IAPs have been proposed as targets for anticancer therapy and a number of peptidomimetic IAP antagonists have entered clinical trials. Using our fragment-based screening approach, we identified non-peptidic fragments binding with millimolar affinities to both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked...


Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site.

To further elucidate the structural activity correlation of glucocorticoid receptor (GR) antagonism, the crystal structure of the GR ligand-binding domain (GR LBD) complex with a non-steroidal antagonist, compound 8, was determined. This novel indole sulfonamide shows in vitro activity comparable to known GR antagonists such as mifepristone and notably this molecule lowers LDL (-74%) and raises HDL (+73%) in a hamster model of dyslipidemia. This is the first reported crystal structure of the GR LBD bound to...

Sunday 29th September 1303

Systematic Backbone Conformational Constraints on a Cyclic Melanotropin Ligand Leads to Highly Selective Ligands for Multiple Melanocortin Receptors.

Human melanocortin receptors (hMCRs) have been challenging targets to develop ligands that are explicitly selective for each of their subtypes. To modulate the conformational preferences of the melanocortin ligands and improve the biofunctional agonist/antagonist activities and selectivity's we have applied a backbone N-methylation approach on Ac-Nle-c[Asp-His-D-Nal(2')-Arg-Trp-Lys]-NH2 (Ac-Nle4-c[Asp5,D-Nal(2')7,Lys10]-NH2), a non-selective cyclic peptide antagonist at the hMC3R and hMC4R, and agonist at t...


Correction to Fragment-Based Discovery of Indole Inhibitors of Matrix Metalloproteinase-13.

Wednesday 19th September 1302

Role of lipoylation of the immunodominant epitope of Pyruvate Dehydrogenase Complex: toward a peptide-based diagnostic assay for Primary Biliary Cirrhosis.

Primary Biliary Cirrhosis is an immune-mediated chronic liver disease whose diagnosis relies on the detection of serum anti-mitochondrial antibodies directed against a complex set of proteins, among which pyruvate dehydrogenase complex is considered the main autoantigen. We studied the immunological role of the lipoyl domain of this protein using synthetic lipoylated peptides, showing that the lipoyl chain chirality does not affect autoantibody recognition and, most importantly, confirming that both lipoyla...

Wednesday 30th May 1302

Enthalpic Forces Correlate with Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma.

The plasma protein transthyretin (TTR) is linked to human amyloidosis. Dissociation of its native tetrameric assembly is a rate-limiting step in the conversion from a native structure into a pathological amyloidogenic fold. Binding of small molecule ligands within the thyroxine binding site of TTR can stabilize the tetrameric integrity and are a potential therapeutic approach. However, through the characterization of nine different tetramer-stabilizing ligands we found that unspecific binding to plasma comp...


Introduction of peripheral carboxylates to decrease the charge on Tm3+ DOTAM-alkyl complexes: Implications for de-tection sensitivity and in vivo toxicity of PARACEST MRI contrast agents.

A series of structurally modified Tm3+ DOTAM-alkyl complexes as potential PARACEST MRI contrast agents has been synthesized with the aim to decrease the overall positive charge associated with these molecules and increase their biocompatibility. Two types of structural modification have been performed, an introduction of terminal carboxylate arms to the alkyl side chains and a conjugation of one of the alkyl side chains with aspartic acid. Detailed evaluation of the magnetic resonance imaging chemical excha...


N-Lipidated Peptide Dimers: Effective Antibacterial Agents against Gram-Negative Pathogens through Lipopolysaccharide Permeabilization.

Treating infections caused by multidrug-resistant Gram-negative pathogens is challenging, and there is concern regarding the toxicity of the most effective antimicrobials for Gram-negative pathogens. We hypothesized that conjugating a fatty acid moiety onto a peptide dimer could maximize the interaction with lipopolysaccharide (LPS) and facilitate the permeabilization of the LPS barrier, thereby improving potency against Gram-negative pathogens. We systematically designed a series of N-lipidated peptide dim...

Monday 28th September 1299

Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1).

Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The op...

Sunday 19th April 1299

Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway.

The kynurenine pathway is responsible for the metabolism of more than 95% of dietary tryptophan and produces numerous bioactive metabolites. Recent studies have focused on three enzymes in this pathway: indoleamine dioxygenase (IDO1), kynurenine monooxygenase (KMO), and kynurenine aminotransferase II (KATII). IDO1 inhibitors are currently in clinical trials for the treatment of cancer, and these agents may also have therapeutic utility in neurological disorders, including multiple sclerosis. KMO inhibitors ...


Distinct Temporal Fingerprint for Cyclic Adenosine Monophosphate (cAMP) Signaling of Indole-2-carboxamides as Allosteric Modulators of the Cannabinoid Receptors.

ORG27569 (1) is an allosteric modulator of CB1. 1 produces a distinct cAMP temporal fingerprint with complex time-dependent modulation of agonist-mediated responses. The aim of this study was to characterize the cAMP signaling response of indole-2-carboxamides structurally correlated to 1 for both CB1 and CB2. We show that at CB1 1, 10, 13, and 18 display a delay in inhibiting CP55,940-mediated cAMP inhibition, whereas compounds 7, 14, 15, 16, 20, and 22 act immediately. To further characterize this, compou...


High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice.

The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clinical use. Herein, we report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset ...

Thursday 27th November 1298

Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX using Structure-Activity Relationships of Glucosyl-Based Sulfamates.

Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be therapeutically advantageous for treating many types of highly aggressive cancers. However, designing selective inhibitors for hCA IX has been difficult due to its high structural homology and sequence similarity with off-target hCAs. Recently the use of glucosyl sulfamate inhibitors has shown promise as selective inhibitors for hCA IX. In this study we present five X-ray crystal structures, determined to a resolution of 1.7 Å or better, of...

Friday 27th June 1298

Tri-block Conjugates: Identification of a Highly Potent Anti-inflammatory Agent.

Rationally designed conjugates of chrysin, indole and barbituric acid were synthesized and screened for their anti-inflammatory activities through in-vitro and in-vivo experiments. Improved over the previously reported chrysin-indole-pyrazole conjugates and also in comparison to the chrysin, indole and barbituric acid based COX-2 inhibitors; the new compounds have displayed significantly better IC50 for COX-2 and some of them also exhibited inhibition of 5-LOX enzyme. For one of the test compounds, IC50 for...

Thursday 16th January 1298

Novel Resveratrol-based Aspirin Prodrugs: Synthesis, Metabolism, and Anticancer Activity.

Regular aspirin use has been convincingly shown to reduce the risk of colorectal cancer. However, long-term use of aspirin leads to gastrotoxicity. Herein, we designed and synthesized a novel class of resveratrol-based aspirin prodrugs to simultaneously release aspirin and resveratrol to attenuate the side effects caused by aspirin. Prodrug RAH exerted enhanced anticancer activities which are better than a physical mixture of aspirin and resveratrol as well as each individual. Metabolism of RAH in mice show...


The Effect of Chirality on Common In Vitro Experiments: An Enantiomeric Pair Analysis.

This analysis elucidates the impact of small molecule architecture on common in vitro ADME assays. In vitro parameters considered in this analysis included Caco-2 permeability/efflux, CYP3A4 inhibition, hERG inhibition and rat microsomal extraction ratio (ER). The statistical significance and practical meaningfulness of chirality was determined by comparison of the distribution of enantiomers with the experimental variation distribution observed from duplicate measurements. Statistical tools were applied to...

Thursday 24th January 1297

Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid.

Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, r...