RÉSUMÉ
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.
Sujet(s)
Antinéoplasiques/pharmacologie , Marqueurs biologiques/métabolisme , Conception de médicament , Protéines du choc thermique HSP90/antagonistes et inhibiteurs , Lactames macrocycliques/synthèse chimique , Lactames macrocycliques/pharmacologie , Animaux , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cristallographie aux rayons X , Colorants fluorescents/synthèse chimique , Colorants fluorescents/composition chimique , Colorants fluorescents/pharmacologie , Humains , Concentration inhibitrice 50 , Lactames macrocycliques/composition chimique , Modèles moléculaires , Structure moléculaire , ortho-Aminobenzoates/synthèse chimique , ortho-Aminobenzoates/composition chimique , ortho-Aminobenzoates/pharmacologieRÉSUMÉ
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
Sujet(s)
Antinéoplasiques/composition chimique , Benzamides/composition chimique , Protéines du choc thermique HSP90/antagonistes et inhibiteurs , Antinéoplasiques/synthèse chimique , Antinéoplasiques/pharmacologie , Benzamides/synthèse chimique , Benzamides/pharmacologie , Sites de fixation , Lignée cellulaire tumorale , Prolifération cellulaire , Simulation numérique , Cristallographie aux rayons X , Conception de médicament , Protéines du choc thermique HSP90/métabolisme , Humains , Liaison aux protéines , Relation structure-activitéRÉSUMÉ
A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamine-based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer.
Sujet(s)
Inhibiteurs de protéines kinases/pharmacologie , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Pyridines/pharmacologie , 3-Phosphoinositide-dependent protein kinases , Cristallographie aux rayons X , Liaison hydrogène , Modèles moléculaires , Structure moléculaire , Inhibiteurs de protéines kinases/composition chimique , Pyridines/composition chimique , Électricité statique , Relation structure-activitéRÉSUMÉ
A series of 4-indolylamino-5-phenyl-3-pyridinecarbonitrile inhibitors of PKCtheta were synthesized as potential anti-inflammatory agents. The effects of specific substitution on the 5-phenyl moiety and variations of the positional isomers of the 4-indolylamino substituent were explored. This study led to the discovery of compound 12d, which had an IC(50) value of 18nM for the inhibition of PKCtheta.
Sujet(s)
Isoenzymes/antagonistes et inhibiteurs , Protéine kinase C/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/synthèse chimique , Pyridines/synthèse chimique , Adénosine triphosphate/composition chimique , Animaux , Anti-inflammatoires/pharmacologie , Chimie pharmaceutique/méthodes , Conception de médicament , Humains , Concentration inhibitrice 50 , Isoenzymes/composition chimique , Souris , Modèles chimiques , Structure moléculaire , Isoformes de protéines , Protéine kinase C/composition chimique , Protein Kinase C-theta , Inhibiteurs de protéines kinases/pharmacologie , Pyridines/pharmacologie , Relation structure-activitéRÉSUMÉ
A series of 4-dimethylamino-but-2-enoic acid [4-(3,6-dioxo-cyclohexa-1,4-dienylamino)-7-ethoxy-quinazolin-6-yl]-amide derivatives were prepared. These compounds have two independent reactive centers and were designed to function as dual irreversible inhibitors of the kinase domains of both Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) where each reactive center targets a different, non-conserved, cysteine residue located in the ATP binding pocket of these enzymes. The compounds contain a 6-(4-(dimethylamino) crotonamide) Michael acceptor group that targets Cys-773 in EGFR and a 4-(amino-[1,4]benzoquinone) moiety that targets Cys-1045 in VEGFR-2. In vitro studies indicated that most of these compounds are relatively potent inhibitors of each enzyme. These inhibitors were compared with reference compounds that lack one or both of the reactive centers. The relative dependence of the IC(50) values on the concentration of ATP used in the assays suggests that these compounds appear to function as irreversible inhibitors of each kinase.
Sujet(s)
Récepteurs ErbB/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Quinazolines/composition chimique , Quinazolines/pharmacologie , Récepteur-2 au facteur croissance endothéliale vasculaire/antagonistes et inhibiteurs , Adénosine triphosphate/composition chimique , Adénosine triphosphate/métabolisme , Sites de fixation , Dosage biologique , Cellules cultivées , Récepteurs ErbB/composition chimique , Récepteurs ErbB/métabolisme , Humains , Concentration inhibitrice 50 , Modèles moléculaires , Structure moléculaire , Conformation des protéines/effets des médicaments et des substances chimiques , Inhibiteurs de protéines kinases/synthèse chimique , Quinazolines/synthèse chimique , Récepteur-2 au facteur croissance endothéliale vasculaire/composition chimique , Récepteur-2 au facteur croissance endothéliale vasculaire/métabolismeRÉSUMÉ
A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,4]benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.
Sujet(s)
Inhibiteurs de l'angiogenèse/synthèse chimique , Benzoquinones/synthèse chimique , Quinazolines/synthèse chimique , Récepteur-2 au facteur croissance endothéliale vasculaire/antagonistes et inhibiteurs , Adénosine triphosphate/métabolisme , Inhibiteurs de l'angiogenèse/composition chimique , Inhibiteurs de l'angiogenèse/pharmacologie , Animaux , Benzoquinones/composition chimique , Benzoquinones/pharmacologie , Sites de fixation , Lignée cellulaire , Femelle , Glutathion/composition chimique , Humains , Cinétique , Souris , Souris nude , Modèles moléculaires , Conformation moléculaire , Phosphorylation , Liaison aux protéines , Structure tertiaire des protéines , Théorie quantique , Quinazolines/composition chimique , Quinazolines/pharmacologie , Spectrométrie de masse ESI , Spectrométrie de masse MALDI , Relation structure-activité , Récepteur-2 au facteur croissance endothéliale vasculaire/composition chimique , Récepteur-2 au facteur croissance endothéliale vasculaire/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
A growing body of evidence suggests that CRF(1) receptor antagonism offers considerable therapeutic potential in the treatment of diseases resulting from elevated levels of CRF, such as anxiety and depression. A series of novel 1,2,3,7-tetrahydro-6H-purin-6-one and 3,7-dihydro-1H-purine-2,6-dione derivatives was synthesized and evaluated as corticotropin releasing factor-1 (CRF(1)) receptor antagonists. Compounds within this series, represented by compound 12d (IC(50) = 5.4 nM), were found to be highly potent CRF(1) receptor antagonists. In addition, compounds 12d and 12j were determined to be selective CRF(1) antagonists. The synthesis, structure-activity relationships and pharmacokinetic properties of compounds within this series is presented.