RESUMO
Synthesis of a series of fused pyrazole tetrahydrofluorenone analogs which are potent, ERbeta subtype selective ligands is described. Analogs possessing subnanomolar ERbeta binding, greater than 100-fold ERbeta-selectivity, and oral bioavailability are reported.
Assuntos
Receptor beta de Estrogênio/efeitos dos fármacos , Fluorenos/química , Pirazóis/química , Animais , Área Sob a Curva , Disponibilidade Biológica , Ciclização , Receptor beta de Estrogênio/metabolismo , Fluorenos/sangue , Fluorenos/metabolismo , RatosRESUMO
Synthesis and derivatization of a series of substituted tetrahydrofluorenone analogs giving potent, ERbeta subtype selective ligands are described. Several analogs possessing ERbeta binding affinities comparable to 17beta-estradiol but with greater than 75-fold selectivity over ERalpha are reported.
Assuntos
Receptor beta de Estrogênio/efeitos dos fármacos , Fluorenos/síntese química , Fluorenos/farmacologia , Linhagem Celular , Cristalografia por Raios X , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor beta de Estrogênio/química , Fluorenos/classificação , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.
Assuntos
Proteínas de Bactérias , Carbapenêmicos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Hexosiltransferases , Peptidil Transferases , Carbapenêmicos/química , Carbapenêmicos/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Resistência Microbiana a Medicamentos , Testes de Sensibilidade Microbiana , Muramilpentapeptídeo Carboxipeptidase/efeitos dos fármacos , Muramilpentapeptídeo Carboxipeptidase/metabolismo , Proteínas de Ligação às PenicilinasRESUMO
A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.
Assuntos
Carbapenêmicos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Lactamas/farmacologia , Tiazóis/farmacologia , Animais , Carbapenêmicos/química , Carbapenêmicos/farmacologia , Carbapenêmicos/toxicidade , Resistência Microbiana a Medicamentos , Humanos , Lactamas/química , Lactamas/farmacocinética , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.