RESUMO
A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC(50) values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Tiofenos/química , Tiofenos/síntese química , Linhagem Celular Tumoral , Proliferação de Células , Cristalização , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Synthesis of C(12) des-methyl ketolide is developed featuring an intramolecular epoxide formation/elimination process to establish the C(12) stereocenter. These ketolides are potent against several key respiratory pathogens, including erythromycin resistant erm- and mef-containing strains of Streptococcus pneumoniae.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Carbono/química , Cetolídeos/química , Cetolídeos/farmacologia , Antibacterianos/química , Cocos Gram-Positivos/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Cetolídeos/síntese química , Metilação , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A novel series of C(12) ethyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens, including those resistant to erythromycin. The C(12) modification involves replacing the natural C(12) methyl group in the erythromycin core with an ethyl group via chemical synthesis. From the C(12) ethyl macrolide core, a series of C(12) ethyl ketolides were prepared and tested for antibacterial activity against a panel of relevant clinical isolates. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria, whether resistance was due to ribosome methylation (erm) or efflux (mef). In particular, the C(12) ethyl ketolides 4k,4s,4q,4m, and 4t showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. The in vivo efficacy of several C(12) ethyl ketolides was demonstrated in a mouse infection model with Streptococcus pneumoniae as pathogen.
Assuntos
Antibacterianos/farmacologia , Eritromicina/farmacologia , Cetolídeos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Eritromicina/análogos & derivados , Eritromicina/síntese química , Cetolídeos/síntese química , Metilação , Camundongos , Testes de Sensibilidade Microbiana , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Ribossomos/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.
