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18:32 EDT 30th August 2015 | BioPortfolio

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Showing PubMed Articles 1–25 of 2,200+ from Journal of medicinal chemistry

Thursday 14th May 1327

Novel C,N-cyclometalated Benzimidazole Ruthenium(II) and Iridium(III) Complexes as Antitumor and Antiangiogenic Agents: a Structure-Activity Relationship Study.

A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(η6-p-cymene)RuCl(κ2-N,C-L)] and [(η5-C5Me5)IrCl(κ2-N,C-L)] (HL = methyl 1-butyl-2-arylbenzimidazole carboxylate) with varying substituents (H, Me, F, CF3, MeO, NO2, and Ph) in the R4 position of the phenyl ring of 2-phenyl-benzimidazole chelating ligand of the ruthenium (3a-3g) and iridium complexes (4a-4g) have been prepared. The cytotoxic activity of the new ruthenium(II) and iridium(III) compoun...

Tuesday 20th January 1327

Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI).

Recent reports suggest that an increasing number of patients with lung cancer, especially those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases (BM) and leptomeningeal metastases (LM). These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their standard dose. Herein we report the discovery of (4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyqui...

1326933

Pan Assay Interference Compounds (PAINS) and other promiscuous compounds in antifungal research.

Every week, articles disclosing new antifungal leads reported as promising starting points for optimization projects are published. In many cases, the mechanism which accounts for their antifungal activity has not been fully elucidated. More significantly, the detrimental impact that could result from certain embedded chemical features has been underestimated or even overlooked. In the course of our research in the agrochemical area, we have concluded that in many cases such leads are actually non-optimizab...

1326845

Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-Substituted-2-Aminobicyclo3.1.0hexane-2,6-Dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo3.1.0hexane-2,6-dicarboxylic acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.

Identification of orthosteric mGlu2/3 receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. Based on second messenger responses in cells expressing recombinant human mGlu2/3 subtype...

Tuesday 6th May 1326

A novel continuous assay for the deacylase Sirtuin 5 and other deacetylases.

Sirtuins are NAD+ dependent lysine deacylases involved in many regulatory processes like control of metabolic pathways, DNA repair and stress response. Modulators of sirtuin activity are needed as tools for uncovering the biological function of these enzymes and as potential therapeutics. Systematic discovery of such modulators is hampered by the lack of efficient and simple continuous activity assays running at low sirtuin concentrations in microtiter plates. Here we describe an improved continuous sirtuin...

Wednesday 5th February 1326

Probing the Backbone Function of Tumor Targeting Peptides by an Amide-to-Triazole Substitution Strategy.

Novel backbone-modified radiolabeled analogs based on the tumor targeting peptide bombesin were synthesized and fully evaluated in vitro and in vivo. We have recently introduced the use of 1,4-disubstituted, 1,2,3-triazoles as metabolically stable trans-amide bond surrogates in radiolabeled peptides in order to improve their tumor targeting. As an extension of our approach, we now report several backbone-modified analogs of the studied bombesin peptide bearing multiple triazole substitutions. We investigate...

1325949

6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel D-Amino Acid Oxidase Inhibitors.

A series of 2-substituted 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione derivatives were synthesized as inhibitors of D-amino acid oxidase (DAAO). Many compounds in this series were found to be potent DAAO inhibitors with IC50 values in the double-digit nanomolar range. The 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione pharmacophore appears metabolically resistant to O-glucuronidation unlike other structurally related DAAO inhibitors. Among them, 6-hydroxy-2-(naphthalen-1-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione 1...

1324504

Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies.

Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very...

Saturday 21st January 1324

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinostide-3-Kinase Delta for the Treatment of Respiratory Disease.

Optimisation of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant Brown Norway Rat acute OVA model of Th2-driven lung inflammation.

1323911

Structure-based design of a small molecule CD4-antagonist with broad spectrum anti-HIV-1 activity.

Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide mid-region, previously...

1322983

Identification of phenoxyalkylbenzimidazoles with anti-tubercular activity.

we conducted an evaluation of the phenoxyalkylbenzimidazole series based on the exemplar 2-ethyl-1-(3-phenoxypropyl)-1H-benzo[d]imidazole for its anti-tubercular activity. Four segments of the molecule were examined systematically to define a structure-activity relationship with respect to biological activity. Compounds had sub-micromolar activity against Mycobacterium tuberculosis; the most potent compound had a minimum inhibitory concentration (MIC) of 52 nM and was not cytotoxic against eukaryotic cells ...

1322917

An Aggregation Advisor for Ligand Discovery.

Colloidal aggregation of organic molecules is the dominant mechanism for artifactual inhibition of proteins, and controls against it are widely deployed. Notwithstanding an increasingly detailed understanding of this phenomenon, a method to reliably predict aggregation has remained elusive. Correspondingly, active molecules that act via aggregation continue to be found in early discovery campaigns, and remain common in the literature. Over the last decade, over twelve thousand aggregating organic molecules ...

1322814

Mitochondria and DNA Targeting 5, 10, 15, 20-Tetrakis(7-sulfonatobenzobthiophene) Porphyrin induced Photodynamic Therapy via Intrinsic and Extrinsic Apoptotic Cell Death.

Photodynamic therapy (PDT) selectively targets subcellular organelles and promises an excellent therapeutic strategy for cancer treatment. Here, we report the synthesis of a new water-soluble photosensitizer, 5, 10, 15, 20-Tetrakis (7-sulfonatobenzo[b]thiophene) Porphyrin (SBTP). Rational design of the porphyrinic molecule containing Benzo[b]thiophene moiety at the meso-position led to selective accumulation in both mitochondria and nucleus of MCF-7 cells. This multi-target ability of SBTP can cause damage ...

Saturday 3rd July 1322

Selexipag: an oral and selective IP prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension.

Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogs is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel non-prostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agoni...

Thursday 18th March 1322

Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists with in Vivo Activity.

We report here a novel series of benzimidazole sulfonamides that act as antagonists of the S1P1 receptor, identified by exploiting an understanding of the pharmacophore of an HTS-derived series of compounds described previously. Lead compound 2 potently inhibits S1P-induced receptor internalization in a cell-based assay (EC50 = 0.05 µM), but has poor physical properties and metabolic stability. Evolution of this compound through structure-activity relationship development and property optimization led to i...

1320868

Rational design of orthogonal multipolar interactions with fluorine in protein-ligand complexes.

Multipolar interactions involving fluorine and protein backbone have been frequently observed in protein-ligand complexes. Such fluorine-backbone interactions may substantially contribute to high affinity of small molecule inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in thienopyrimidine class of menin-MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of me...

1320810

Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3.

To realize the medicinal potential of peptide toxins-naturally occurring disulfide-rich peptides-as ion channel antagonists, more efficient pharmaceutical optimization technologies must be developed. Here we show that the therapeutic properties of multiple cysteine toxin peptides can be rapidly and substantially improved by combining direct chemical strategies with high-throughput electrophysiology. We applied whole-molecule, brute-force, structure-activity analoging to ShK, a peptide toxin from the sea ane...

1320760

Medicinal Chemistry Approaches to Heart Regeneration.

Due to the minimal and clearly insufficient ability of the adult heart to regenerate after ischemic injury, there is a great opportunity to identify biological mechanisms, substances and factors that enhance this process. Hence, innovative therapeutic management of heart failure following infarction requires a paradigm shift in pharmacotherapy. Spurred by tremendous progress in the field of stem cell and cardiac biology, several attractive approaches for regeneration of lost cardiomyocytes and supporting va...

1320682

The Discovery And Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid, An Improved PDE4 Inhibitor For The Treatment of Chronic Obstructive Pulmonary Disease (COPD).

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2: 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)cyclohexanecarboxylic acid. Compound 2 was found to have exemplary pharmacokinetics in humans, which enabled a novel dosing regime and the achievement of high plasma drug levels without associated nausea or emesis.

1316697

Targeting Drug Resistance in EGFR with Covalent Inhibitors - a Structure-Based Design Approach.

Receptor tyrosine kinases represent one of the prime targets in cancer therapy as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time to EGFR by alkylating Cys797 and thereby preventing toxic effects. Here...

Thursday 22nd January 1316

Discovery of Potent and Selective RSK Inhibitors as Biological Probes.

While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, the full understanding of this kinase family has been restricted by the lack of highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor of the N-terminal kinase of RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted in highly optimized difluorophenol pyridine inhibitors of the RSK kinase fami...

1315895

Fragments Can Bind Either More Enthalpy or Entropy-Driven: Crystal Structures and Residual Hydration Pattern Suggest Why.

In lead optimization small enthalpically advantaged fragments have been suggested superior as an entropic component will be added inevitably during late-stage optimization. Determination of thermodynamic signatures of weak-binding fragments are essential to support the decision-making process which fragment to take to further optimization. High-resolution crystal structures of six fragments binding to the S1-pocket of thrombin were determined and analyzed with respect to their thermodynamic profile. Two mos...

1314997

Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists.

Orexins are a family of neuropeptides that regulate sleep/wakefulness, acting on two G protein-coupled receptors, orexin receptors-1 (OX1R) and -2 (OX2R). Genetic and pharmacologic evidence suggests that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy. We herein report the discovery of a potent (EC50 on OX2R = 0.023 µM) and OX2R-selective (OX1R/OX2R EC50 ratio = 70) agonist, 4'-methoxy-N,N-dimethyl-3'-[N-(3-{[2-(3-methylbe...

1314897

Discovery of 4-Amino-8-quinoline carboxamides as novel, submicromolar inhibitors of the NAD hydrolyzing enzyme CD38.

Starting from the micromolar 8-quinoline carboxamide high throughput screening hit 1a, a systematic exploration of the structure/activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1...

Friday 4th October 1314

High Sensitive Near-Infrared Fluorophores for in Vivo Detection of Amyloid-β Plaques in Alzheimer's Disease.

Alzheimer's disease (AD) is pathologically characterized by the accumulation of β-amyloid (Aβ) deposits in the parenchymal and cortical brain. In this article, we designed, synthesized and evaluated a series of near-infrared (NIR) probes with electron donor-acceptor end groups interacting through a π-conjugated system for the detection of Aβ deposits in the brain. Among these probes, 3b and 3c had excellent fluorescent properties (emission maxima > 650 nm and high quantum yields) and displayed high sens...



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