articles+ search results

Biochemistry, molecular biology, biophysics, Biochimie, biologie moléculaire, biophysique, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Enzyme, Enzima, Oxidoreductases, Dérivé de l'isoquinoléine, Isoquinoline derivatives, Isoquinoleína, Homme, Human, Hombre, Inhibiteur, Inhibitor, Inhibidor, Prostaglandin-endoperoxide synthase, Site fixation, Binding site, Sitio fijación, Isoquinoline, PGDS inhibitors, Prostaglandin D2 synthase, and Water displacement

The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme. The study provides insight into the binding requirements for the design of potent hH-PGDS inhibitors.

Biochemistry, molecular biology, biophysics, Biochimie, biologie moléculaire, biophysique, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Os, articulations et tissu conjonctif. Antiinflammatoires, Bones, joints and connective tissue. Antiinflammatory agents, Activité biologique, Biological activity, Actividad biológica, Amine, Amina, Appareil circulatoire, Circulatory system, Aparato circulatorio, Canal ionique, Ionic channel, Canal iónico, Chimiokine, Chemokine, Quimioquina, Dofétilide, Dofetilide, Dofetilida, Dérivé du cyclopentane, Cyclopentane derivatives, Ciclopentano derivado, Dérivé du pyrane, Pyran derivatives, Pirano derivado, Fixation biologique, Biological fixation, Fijación biológica, Fluor Composé organique, Fluorine Organic compounds, Fluor Compuesto orgánico, Interaction moléculaire, Molecular interaction, Interacción molecular, Protéine MCP1, Monocyte chemoattractant protein 1, Proteina quimiocaptante monocitos 1, Récepteur chimiokine CCR2, CCR2 chemokine receptor, Receptor quimioquina CCR2, Synthèse chimique, Chemical synthesis, Síntesis química, Toxicité, Toxicity, Toxicidad, 2,5-Diazabicyclo[2.2.1]heptane dérivé, Canal hERG, Canal potassium, Cardiotoxicité, Stabilité métabolique, Metabolic stability, CCR2 antagonists, Central penetrance, Diazobicyclo[2.2.1]heptane, Fluoropyran, Inflammatory diseases, MCP-1, Neuropathic pain, and hERG

This report describes the design and synthesis of a series of CCR2 antagonists incorporating novel non-aryl/heteroaryl RHS (right hand side) motifs. Previous SAR in the area has suggested an aryl/ heteroaryl substituent as a necessary structural feature for binding to the CCR2 receptor. Herein we describe the SAR with regards to potency (binding to hCCR2), dofetilide activity and metabolic stability (in vitro HLM) for this series. The resulting outcome was the identification of compounds with excellent properties for the investigation of the role of CCR2 in disease.

Biochemistry, molecular biology, biophysics, Biochimie, biologie moléculaire, biophysique, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Os, articulations et tissu conjonctif. Antiinflammatoires, Bones, joints and connective tissue. Antiinflammatory agents, Enzyme, Enzima, Transferases, Amine aromatique, Aromatic amine, Amina aromática, Complexe enzyme inhibiteur, Inhibitor enzyme complex, Complejo enzima inhibidor, Composé aromatique, Aromatic compound, Compuesto aromático, Dérivé de l'aniline, Aniline derivatives, Anilina derivado, Dérivé de l'indazole, Indazole derivatives, Indazol derivado, Dérivé de la pipérazine, Piperazine derivatives, Piperazina derivado, Facteur transcription NFκB, Transcription factor NFκB, Factor transcripción NFκB, Hétérocycle azote, Nitrogen heterocycle, Heterociclo nitrógeno, In vitro, Inhibiteur enzyme, Enzyme inhibitor, Inhibidor enzima, Isozyme, Isozima, Modèle moléculaire, Molecular model, Modelo molecular, Modélisation, Modeling, Modelización, Protein kinase C, Relation structure activité, Structure activity relation, Relación estructura actividad, Synthèse chimique, Chemical synthesis, Síntesis química, Sélectivité, Selectivity, Selectividad, Benzimidazole(2-[6-(4-aminophényl)indazol-3-yl]-4-[4-méthylpipérazino]), CDK-2, Indazole, NF-Kb, PKC isoforms, PKC-ζ, Surrogate kinases, and X-ray crystallography

The inhibition of PKC-ζ has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-lH-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-ζ). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH2 derivative. The analog displays good selectivity over other PKC isoforms (α, pll, y, δ, ε, μ, 6, η and 1/λ) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).

Biochemistry, molecular biology, biophysics, Biochimie, biologie moléculaire, biophysique, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Os, articulations et tissu conjonctif. Antiinflammatoires, Bones, joints and connective tissue. Antiinflammatory agents, Cancer, Cáncer, Enzyme, Enzima, Hémopathie maligne, Malignant hemopathy, Hemopatía maligna, Immunopathologie, Immunopathology, Inmunopatología, Lymphome non hodgkinien, Non Hodgkin lymphoma, Linfoma no Hodgkin, Maladie autoimmune, Autoimmune disease, Enfermedad autoinmune, Mammalia, Pathologie du système ostéoarticulaire, Diseases of the osteoarticular system, Sistema osteoarticular patología, Rhumatisme inflammatoire, Inflammatory joint disease, Reumatismo inflamatorio, Rodentia, Syndrome lymphoprolifératif, Lymphoproliferative syndrome, Linfoproliferativo síndrome, Transferases, Vertebrata, Acide carboxylique, Carboxylic acid, Acido carboxílico, Animal, Antiinflammatoire, Antiinflammatory agent, Antiinflamatorio, Cellule tumorale, Tumor cell, Célula tumoral, Chronique, Chronic, Crónico, Cytokine, Citoquina, Dérivé de la carboline, Carboline derivatives, Facteur nécrose tumorale α, Tumor necrosis factor α, Factor necrosis tumoral α, Homme, Human, Hombre, In vitro, In vivo, Inflammation, Inflamación, Inhibiteur enzyme, Enzyme inhibitor, Inhibidor enzima, Lignée cellulaire, Cell line, Línea celular, Lymphome histiocytaire, Histiocytic lymphoma, Linfoma histiocitario, Mitogen-activated protein kinase, Non-specific serine/threonine protein kinase, Polyarthrite rhumatoïde, Rheumatoid arthritis, Poliartritis reumatoidea, Production, Producción, Rat, Rata, Relation structure activité, Structure activity relation, Relación estructura actividad, Synthèse chimique, Chemical synthesis, Síntesis química, Sélectivité, Selectivity, Selectividad, Transduction signal, Signal transduction, Transducción señal, 2,5-Méthanoazépino[3,4-b]indole-1-carboxylique acide(7-méthoxy-1,2,3,4-tétrahydro), Lignée U937, Méthanoazépinoindole, Pyrido[3,4-b]indole dérivé, Pyrido[3,4-b]indole-1-carboxylique acide dérivé, Pyridoindole, β-Carboline dérivé, MAPKAP kinase 2, MK-2, TNF-a, and β-Carboline-1

-A structure-activity relationship study was conducted on a series of tetrahydro-β-carboline-1-carboxylic acid analogs in order to identify the key functionality responsible for activity against the mitogen-activated protein kinase-activated protein kinase 2 enzyme (MK-2). The compounds were further evaluated for their ability to inhibit TNFα production in U937 cells and in vivo. These compounds represent a novel structural class of compounds capable of inhibiting MK-2 with remarkable selectivity.

Biochemistry, molecular biology, biophysics, Biochimie, biologie moléculaire, biophysique, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Sang. Coagulation sanguine. Système réticuloendothélial, Blood. Blood coagulation. Reticuloendothelial system, Enzyme, Enzima, Hydrolases, Mammalia, Pathologie de l'appareil circulatoire, Cardiovascular disease, Aparato circulatorio patología, Pathologie des vaisseaux sanguins, Vascular disease, Vaso sanguíneo patología, Peptidases, Rodentia, Serine endopeptidases, Vertebrata, Activité enzymatique, Enzymatic activity, Actividad enzimática, Amidine, Amidina, Animal, Anticoagulant, Anticoagulante, Antithrombotique, Antithrombotic agent, antitrombōtico, Basicité, Alkalinity, Alcalinidad, Biodisponibilité, Bioavailability, Biodisponibilidad, Chlore Composé organique, Chlorine Organic compounds, Cloro Compuesto orgánico, Coagulation Factor VIIa, Constante dissociation, Dissociation constant, Constante disociación, Dérivé de la pyrazine, Pyrazine derivatives, Pirazina derivado, Facteur tissulaire, Tissue factor, Factor tisular, Inhibiteur enzyme, Enzyme inhibitor, Inhibidor enzima, Intestin, Gut, Intestino, Pharmacocinétique, Pharmacokinetics, Farmacocinética, Propriété chimique, Chemical properties, Propiedad química, Rat, Rata, Relation structure activité, Structure activity relation, Relación estructura actividad, Synthèse chimique, Chemical synthesis, Síntesis química, Thrombose, Thrombosis, Trombosis, Voie orale, Oral administration, Vía oral, Benzamidine dérivé, Pyrazine-1-acétamide dérivé, Pyrazinone dérivé, Anticoagulants, Antithrombotics, Factor VIIa, Oral, Pyrazinones, Serine protease, and TF/VIIa

-Herein is described the design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors were designed to explore replacement and variation of the P1 amidine described previously [J. Med. Chem. 2003, 46, 4050]. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (pKa ∼ 12). A contributing factor towards the oral bioavailability of a compound is the ionization state of the compound in the intestinal tract. The desired outcome of the study was to identify an orally bioavailable TF-VIIa inhibitor.