RESUMO
Tumor angiogenesis is mediated by KDR and other VEGFR and PDGFR kinases. Their inhibition presents an attractive approach for developing anticancer therapeutics. Here, we report a series of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors. A number of compounds have been identified to be orally bioavailable and efficacious in the mouse edema model.
Assuntos
Aminopiridinas/química , Aminopiridinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Aminopiridinas/síntese química , Aminopiridinas/farmacocinética , Animais , Disponibilidade Biológica , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Concentração Inibidora 50 , Camundongos , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacologia , Doenças Uterinas/tratamento farmacológico , Doenças Uterinas/metabolismoRESUMO
The regulatory regions of 52 erm(A) [formerly erm(TR)] clinical Streptococcus pyogenes isolates were studied. Differences in the upstream regulatory region of erm(A) correlated with macrolide/lincosamide resistance patterns. Nine macrolide/lincosamide/streptogramin B-resistant isolates had changes in the leader sequence of erm(A) including base changes, insertions, or deletions. Isolates were also emm typed.
Assuntos
Proteínas de Bactérias/química , Farmacorresistência Bacteriana/genética , Regulação Bacteriana da Expressão Gênica , Metiltransferases/química , Mutação , Sinais Direcionadores de Proteínas/genética , Streptococcus pyogenes/efeitos dos fármacos , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sequência de Bases , Humanos , Lincosamidas , Macrolídeos/farmacologia , Metiltransferases/genética , Metiltransferases/metabolismo , Testes de Sensibilidade Microbiana , Streptococcus pyogenes/genética , Streptococcus pyogenes/isolamento & purificaçãoRESUMO
A total of 336 Streptococcus pyogenes isolates recently recovered from patients with pharyngitis from 13 countries were characterized by emm typing and riboprinting using an automated Riboprinter (Dupont/Qualicon) based on the patterns produced by three restriction enzymes, EcoRI, PstI, and HindIII. Three enzymes were necessary to increase the discrimination of ribogroups formed by each enzyme. A total of 40 ribogroups and 38 emm sequences (not counting allelic variations) were identified. Multilocus sequence typing was performed on a sampling of the isolates, and those results were consistent with those of both emm typing and ribotyping. Correlations were observed among all three methods.
Assuntos
Antígenos de Bactérias/genética , Proteínas da Membrana Bacteriana Externa/genética , Técnicas de Tipagem Bacteriana , Proteínas de Transporte/genética , Faringite/microbiologia , Ribotipagem , Streptococcus pyogenes/classificação , Antígenos de Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Transporte/metabolismo , Desoxirribonuclease EcoRI/metabolismo , Desoxirribonuclease HindIII/metabolismo , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Humanos , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/genética , Streptococcus pyogenes/isolamento & purificaçãoRESUMO
Twenty macrolide and/or lincosamide resistant Streptococcus pneumoniae clinical isolates from various sources with 50S ribosomal mutations were identified. Mutations were identified in the 23S rDNA with substitutions at A2058, A2059, or C2611 and in L4 or L22 ribosomal protein genes. Fourteen were A2059G substitutions, one was A2058G, two were C2611T, two had an altered L4 and one isolate contained an altered L22 gene. Susceptibility testing with erythromycin, josamycin, clindamycin, and two ketolides including cethromycin was performed. The L4 mutants had the amino acid changes of (69)GTG(71) to (69)TPS(71). The isolate with the L22 mutation contained an 18 base pair tandem duplication/insertion at the 3' end of the gene. 50s ribosomal mutations are the least frequent mechanism of S. pneumoniae resistance, occurring at an extremely low frequency and are identified only by genome sequence data.
Assuntos
Macrolídeos/farmacologia , RNA Ribossômico 23S/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Humanos , Lincosamidas , Testes de Sensibilidade Microbiana , Epidemiologia Molecular , Mutação , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/epidemiologia , RNA Ribossômico 23S/genética , Estudos de Amostragem , Sensibilidade e Especificidade , Streptococcus pneumoniae/genéticaRESUMO
The activity of a new ketolide, ABT-773, was compared to the activity of the ketolide telithromycin (HMR-3647) against over 600 gram-positive clinical isolates, including 356 Streptococcus pneumoniae, 167 Staphylococcus aureus, and 136 Streptococcus pyogenes isolates. Macrolide-susceptible isolates as well as macrolide-resistant isolates with ribosomal methylase (Erm), macrolide efflux (Mef), and ribosomal mutations were tested using the NCCLS reference broth microdilution method. Both compounds were extremely active against macrolide-susceptible isolates, with the minimum inhibitory concentrations at which 90% of the isolates tested were inhibited (MIC90s) for susceptible streptococci and staphylococci ranging from 0.002 to 0.03 microg/ml for ABT-773 and 0.008 to 0.06 microg/ml for telithromycin. ABT-773 had increased activities against macrolide-resistant S. pneumoniae (Erm MIC90, 0.015 microg/ml; Mef MIC90, 0.12 microg/ml) compared to those of telithromycin (Erm MIC90, 0.12 microg/ml; Mef MIC90, 1 microg/ml). Both compounds were active against strains with rRNA or ribosomal protein mutations (MIC90, 0.12 microg/ml). ABT-773 was also more active against macrolide-resistant S. pyogenes (ABT-773 Erm MIC90, 0.5 microg/ml; ABT-773 Mef MIC90, 0.12 microg/ml; telithromycin Erm MIC90, >8 microg/ml; telithromycin Mef MIC90, 1.0 microg/ml). Both compounds lacked activity against constitutive macrolide-resistant Staphylococcus aureus but had good activities against inducibly resistant Staphylococcus aureus (ABT-773 MIC90, 0.06 microg/ml; telithromycin MIC90, 0.5 microg/ml). ABT-773 has superior activity against macrolide-resistant streptococci compared to that of telithromycin.