RESUMEN
The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Ácidos Hidroxámicos/síntesis química , Piridonas/síntesis química , Ácidos Sulfónicos/síntesis química , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Cristalografía por Rayos X , Humanos , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácidos Sulfónicos/farmacocinética , Ácidos Sulfónicos/farmacologíaRESUMEN
When stable atropisomers are encountered by drug discovery teams, they can have important implications due to potential differences in their biological activity, pharmacokinetics, and toxicity. Knowledge of an atropisomer's activation parameters for interconversion is required to facilitate informed decisions on how to proceed. Herein, we communicate the development of a new method for the rapid measurement of atropisomer racemization kinetics utilizing segmented flow technology. This method leverages the speed, accuracy, low sample requirement, safety, and semiautomated nature of flow instrumentation to facilitate the acquisition of kinetics data required for experimentally probing atropisomer activation parameters. Measured kinetics data obtained for the atropo isomerization of AMPA antagonist CP-465021 using segmented flow and traditional thermal methods were compared to validate the method.
RESUMEN
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Compuestos de Bifenilo/síntesis química , Ácidos Hidroxámicos/síntesis química , Éteres Fenílicos/síntesis química , Infecciones por Pseudomonas/tratamiento farmacológico , Sulfuros/síntesis química , Sulfonas/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Dominio Catalítico , Cristalografía por Rayos X , Farmacorresistencia Bacteriana , Enlace de Hidrógeno , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Pseudomonas aeruginosa , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacología , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Diseño de Fármacos , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Piridinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/síntesis química , Inhibidores de Captación Adrenérgica/metabolismo , Inhibidores de Captación Adrenérgica/farmacología , Línea Celular , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos/métodos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Fenoles/síntesis química , Fenoles/metabolismo , Fenoles/farmacología , Piridinas/metabolismo , Piridinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas de Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Imidazole glycerol phosphate dehydratase (IGPD) has become an attractive target for herbicide discovery since it is present in plants and not in mammals. Currently no knowledge is available on the 3-D structure of the IGPD active site. Therefore, we used a pharmacophore model based on known inhibitors and 3-D database searches to identify new active compounds. In vitro testing of compounds from the database searches led to the identification of a class of pyrrole aldehydes as novel inhibitors of IGPD.