RESUMO
Bisphenol A (BPA) is a widely used plasticizer whose estrogenic properties may impact hormone-responsive disorders and fetal development. In vivo, BPA appears to have greater activity than is suggested by its estrogen receptor (ER) binding affinity. This may be a result of BPA sulfation/desulfation providing a pathway for selective uptake into hormone-responsive cells. BPA is a substrate for estrogen sulfotransferase, and bisphenol A sulfate (BPAS) and disulfate are substrates for estrone sulfatase. Although the sulfated xenobiotics bind poorly to the ER, both stimulated the growth of receptor-positive breast tumor cells. Treatment of MCF-7 cells with BPAS leads to desulfation and uptake of BPA. No BPAS is found inside the cells. These findings suggest a mechanism for the selective uptake of BPA into cells expressing estrone sulfatase. Therefore, sulfation may increase the estrogenic potential of xenobiotics.
Assuntos
Neoplasias da Mama/metabolismo , Fenóis/farmacocinética , Sulfotransferases/efeitos dos fármacos , Óxidos de Enxofre/química , Ésteres do Ácido Sulfúrico/farmacocinética , Compostos Benzidrílicos , Sítios de Ligação , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Sensibilidade e Especificidade , Sulfotransferases/química , Sulfotransferases/metabolismo , Ésteres do Ácido Sulfúrico/síntese química , Ésteres do Ácido Sulfúrico/químicaRESUMO
With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.
Assuntos
Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Barbitúricos/farmacologia , Barbitúricos/uso terapêutico , Gonorreia/tratamento farmacológico , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/uso terapêutico , Adulto , Animais , Antibacterianos/química , Barbitúricos/química , DNA Topoisomerases Tipo II/química , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana , Feminino , Fluoroquinolonas/farmacologia , Gonorreia/microbiologia , Haplorrinos , Humanos , Isoxazóis , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Modelos Moleculares , Conformação Molecular , Morfolinas , Mutação , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/genética , Oxazolidinonas , Ratos , Compostos de Espiro/química , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II/química , Adulto JovemRESUMO
The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.
Assuntos
Benzimidazóis/farmacologia , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Composição Corporal , Relação Dose-Resposta a Droga , Camundongos , Modelos Animais , Relação Estrutura-Atividade , Redução de Peso/efeitos dos fármacosRESUMO
Novel 2'-heteroaryl-2-(phenoxymethyl)imidazolines have been identified as potent agonists of the cloned human alpha(1)-adrenoceptors in vitro. The nature of the 2'-heteroaryl group can have significant effects on the potency, efficacy, and subtype selectivity in this series. alpha(1A) Subtype selective agonists have been identified.