RESUMEN
Bacterial DNA gyrase and topoisomerase IV inhibition has emerged as a promising strategy for the cure of infections caused by antibiotic-resistant bacteria. The Novel Bacterial Topoisomerase Inhibitors (NBTIs) bind to a different site from that of the quinolones with novel mechanism of action. This evades the existing target-mediated bacterial resistance associated with quinolones. This article presents our efforts to identify in vitro potent and broad-spectrum antibacterial agent 4l.
Asunto(s)
Antibacterianos , Pruebas de Sensibilidad Microbiana , Piperidinas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Piperidinas/química , Piperidinas/farmacología , Piperidinas/síntesis química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa/farmacología , Inhibidores de Topoisomerasa/química , Inhibidores de Topoisomerasa/síntesis química , Girasa de ADN/metabolismo , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/síntesis química , Topoisomerasa de ADN IV/antagonistas & inhibidores , Topoisomerasa de ADN IV/metabolismo , Estructura Molecular , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
Amino acid restriction by inhibition of neutral amino acid transporter, B0AT1 (SLC6A19) activity has been recently shown to improve glyceamic control by upregulating glucagon like peptide (GLP1) and fibroblast growth factor (FGF21) in mice. Hence, pharmacological inhibition of B0AT1 is expected to treat type-2 diabetes and related disorder. In this study, rationally designed trifluoromethyl sulfonyl derivatives were identified as novel, potent and orally bioavailable B0AT1 inhibitors. Compound 39 was found to be nanomolar potent (IC50: 0.035 µM) B0AT1 inhibitor with excellent pharmacokinetic profile (%F: 66) in mice and efficacious in vivo in diet induced obese (DIO) mice model.
Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/farmacología , Descubrimiento de Drogas , Sulfonamidas/farmacología , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animales , Antiinflamatorios no Esteroideos/química , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED50 of 7.9 mg/kg and ED90 of 29.2 mg/kg.