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11:25 EST 22nd November 2014 | BioPortfolio

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


Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with In Vivo Antithrombotic Activity.

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg/kg/h). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlayed onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achiev...


Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram Positive and Gram Negative Pathogens.

In order to better understand the difficulties surrounding the identification of novel antibacterial compounds from corporate screening collections, physical properties of ~3200 antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found from high throughput (HTS) screens conducted on both biochemical and phenotypic bacterial targets. The output from 23 antibacterial HTS screens illustrated that when compared to the pr...


Discovery of (2S)-8-(3R)-3-Methylmorpholin-4-yl-1-(3-methyl-2-oxo-butyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido1,2-apyrimidin-6-one: a Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors.

Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimido-pyrimidinone derivatives. Starting with hit compound 1, medicinal chemistry ...

Sunday 20th November 1120

Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives.

The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform-selectivity, and pharmacological properties by structure-activity relationship (SAR) studies utilizing biochemical and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38...

Tuesday 23rd August 1120

Binding mode and potency of N-indolyl-oxopyridinyl-4-amino-propanyl-based inhibitors targeting Trypanosoma cruzi CYP51.

Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure-activity relationships (SAR) of an N-arylpiperazine series of N-indolyl-oxopyri...

Tuesday 3rd May 1120

Dicarba Analogues of α-Conotoxin RgIA. Structure, Stability and Activity at Potential Pain Targets.

α-Conotoxin RgIA is an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and also inhibits high voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with non-reducible dicarba bridges. Solution structures were determined b...

Sunday 31st January 1120

Discovery of BI 207524, an indole diamide NS5B thumb pocket 1 inhibitor with improved potency for the potential treatment of chronic HCV infection.

The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compoun...


Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors.

The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of...


Phosphatidylinositol 3-kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: the importance of the morpholine ring.

Phosphatidylinositol 3-kinases (PI3K) and phosphatidylinositol 3-kinase-related protein kinases (PIKK) are two related families of kinases, which play key roles in regulation of cell's proliferation, metabolism, migration, survival and responses to diverse stresses including DNA damage. To design novel efficient strategies for treatment of cancer and other diseases, these kinases have been extensively studied. Despite their different nature, these two kinase families have related origin and share very simil...


Analysis of sub-pocket selectivity and identification of potent selective inhibitors for matriptase and matriptase-2.

We studied the factors affecting the selectivity of peptidomimetic inhibitors of matriptase and matriptase-2 across sub-pockets using docking simulations. We observed that the further away a sub-pocket is located from the catalytic site, the more pronounced its role in selectivity. Additionally, as a result of our exhaustive virtual screening, we identified novel, low nM, selective inhibitors of both enzymes.


Discovery of 2-(Cyclopentylamino)thieno3,2-dpyrimidin-4(3H)-one Derivatives as a New Series of Potent Phosphodiesterase 7 Inhibitors.

The discovery of a new series of potent phosphodiesterase 7 (PDE7) inhibitors is described. Novel thieno[3,2-d]pyrimidin-4(3H)-one hit compounds were identified from our chemical library. Preliminary modifications of the hit compounds were performed, resulting in the discovery of a fragment-sized compound (10) with highly improved ligand efficiency. Compound design was guided by structure-activity relationships and computational modeling. The 6-substituted derivatives of the thienopyrimidinone showed dimini...

Friday 28th June 1117

Discovery of selective and non-covalent diaminopyrimidine based inhibitors of EGFR containing the T790M resistance mutation.

Activating mutations within the EGFR kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in non-small cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose...

Thursday 25th April 1117

Chroman-4-one- and Chromone-based Sirtuin 2 Inhibitors with Antiproliferative Properties in Cancer Cells.

Sirtuins (SIRTs) catalyze the NAD+-dependent deacetylation of N-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The...

Sunday 27th January 1117

Discovery of Pentacyclic Triterpenoids as Potential Entry Inhibitors of Influenza Viruses.

Entry inhibitors are of particular importance in current efforts to develop a new generation of anti-influenza virus drugs. Here we report certain pentacyclic triterpenes exhibiting conserved structure features and with in vitro anti-influenza virus activity comparable to and even higher than that of oseltamivir. Mechanistic studies indicated that these lead triterpenoids bind tightly to the viral envelope hemagglutinin (HA), disrupting the interaction of HA with the sialic acid receptor and thus the attach...


The Discovery and Optimization of 4,5-Diarylisoxazoles as Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase (PDHK) and Heat Shock Protein 90 (HSP90).

Upregulation of pyruvate dehydrogenase kinase (PDHK) has been observed in a variety of cancers. Inhibition of PDHK offers an attractive opportunity for the development of novel cancer therapies. To obtain novel PDHK inhibitors, we took advantage of the homology of the ATP-binding pocket between HSP90 and PDHK, and utilized 4,5-diarylisoxazole based HSP90 inhibitor for structural design. Our efforts led to the identification of 5k that inhibited PDHK1 with an IC50 value of 17 nM, which however, showed margin...


Fluorescent non-peptidic RGD-mimetics with high selectivity for αVβ3 integrin vs. αIIbβ3 receptors: Novel probes for in vivo optical imaging.

Integrins are heterodimeric transmembrane protein receptors consisting of different α and β subunits. αvβ3 Integrins are overexpressed on many tumor cells and tumor-associated angiogenic vessels, while αIIbβ3 is a receptor for e.g. fibrinogen and mediates platelet aggregation. In this study, a near-infrared fluorescent imaging probe has been designed and synthesized by conjugating fluorescent dyes to a non-peptidic, pharmacophore-based ligand, based on a molecular modeling design approach. Affinity va...


Discovery of 1-2-Fluoro-4-(1H-pyrazol-1-yl)phenyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a Highly Potent, Selective, and Orally Active Phosphodiesterase 10A (PDE10A) Inhibitor.

A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors were synthesized. Our optimization efforts using structure-based drug design (SBDD) techniques on the basis of the X-ray crystal structure of PDE10A in complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over other PDEs) led to the identification of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (27h). Compound 27h has potent inhibitory activity (IC50 = 0.30 nM), excel...


Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.

Structure-based rational design and extensive SAR led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with an 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition = 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo anti-tumor activity ...


Discovery Heralds New Approach to the Treatment of Cystic Fibrosis.

Friday 12th August 1115

SAR studies on tetrahydroisoquinoline derivatives: the role of flexibility and bioisosterism to raise potency and selectivity on P-gp protein.

The development of P-glycoprotein (P-gp) ligands remains of considerable interest mostly for investigating protein structure and transport mechanism. In the last years many ligands, belonging to different generations, have been tested for modulating P-gp activity. Aim of the present work is to perform SAR studies on tetrahydroisoquinoline derivatives in order to design potent and selective P-gp ligands. For this purpose the effect of bioisosteric replacement and the role of flexibility have been investigate...


Absolute Quantitative (1)H NMR Spectroscopy for Compound Purity Determination.


Methyl Effect in Azumamides Provides Insight Into Histone Deacetylase Inhibition by Macrocycles.

Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides ( J. Med. Chem. 2013 , 56 , 6512 ). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solvin...


Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic.

FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multi-parametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor, combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-c...


Synthesis, Biological Evaluation, and 3D QSAR Study of 2-Methyl-4-oxo-3-oxetanylcarbamic Acid Esters as N-Acylethanolamine Acid Amidase (NAAA) Inhibitors.

N-(2-oxo-3-oxetanyl)carbamic acid esters have recently been reported to be noncompetitive inhibitors of the N-acylethanolamine acid amidase (NAAA) potentially useful for the treatment of pain and inflammation. In the present study, we further explored the structure activity relationships of the carbamic acid ester side chain of 2-methyl-4-oxo-3-oxetanylcarbamic acid ester derivatives. Additional favourable features in the design of potent NAAA inhibitors have been found together with the identification of a...


Positive Allosteric Modulators of 2‑Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides.

Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to AMPA receptor positive allosteric modulators were co-crystallized with the GluA2 ligand-binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordin...

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