RESUMEN
Optimization of clearance of adenosine inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. To reduce Cytochrome P-450-mediated metabolic clearance, many strategies were explored; however, most modifications resulted in compounds with reduced antibacterial activity and/or unchanged total clearance. The alkyl side chains of the 2-cycloalkoxyadenosines were fluorinated, and compounds with moderate antibacterial activity and favorable pharmacokinetic properties in rat and dog were identified.
Asunto(s)
Adenosina/química , Antibacterianos/síntesis química , ADN Ligasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , NAD/química , Adenina/química , Administración Oral , Animales , Antibacterianos/química , Disponibilidad Biológica , Cromatografía Liquida/métodos , ADN Ligasas/química , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Flúor/química , Concentración 50 Inhibidora , Espectrometría de Masas/métodos , Modelos Químicos , RatasRESUMEN
Optimization of adenosine analog inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. Antibacterial activity against Streptococcus pneumoniae and Staphylococcus aureus was improved by modification of the 2-position substituent on the adenine ring and 3'- and 5'-substituents on the ribose. Compounds with logD values 1.5-2.5 maximized potency and maintained drug-like physical properties.
Asunto(s)
Antibacterianos/química , ADN Ligasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Adenosina/análogos & derivados , Adenosina/síntesis química , Adenosina/farmacología , Antibacterianos/síntesis química , Antibacterianos/farmacología , Sitios de Unión , Cristalografía por Rayos X , ADN Ligasas/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pruebas de Sensibilidad Microbiana , NAD/metabolismo , Estructura Terciaria de Proteína , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
Herein, we report spiropyrimidinetriones (SPTs) incorporating N-linked azole substituents on a benzisoxazole scaffold with improved Gram-positive antibacterial activity relative to previously described analogues. SPTs have an unusual spirocyclic architecture and represent a new antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors. They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase IV inhibitors used clinically. The activity of the SPTs was assessed for DNA gyrase inhibition, and the antibacterial activity across Gram-positive and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted on the 5-position provides the most worthwhile profile. Directed nucleophilic and electrophilic chemistry was developed to vary this 5-position with carbon, nitrogen, or oxygen substituents and explore structure-activity relationships including those around a target binding model. Compounds with favorable pharmacokinetic parameters were identified, and two compounds demonstrated cidality in a mouse model of Staphylococcus aureus infection.
Asunto(s)
Antibacterianos/farmacología , Girasa de ADN/metabolismo , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Inhibidores de Topoisomerasa II/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Azoles/química , Azoles/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Isoxazoles/química , Isoxazoles/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirimidinonas/farmacología , Ratas , Ratas Wistar , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismo , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
An SAR study of an HTS screening hit generated a series of pyridodiazepine amines as potent inhibitors of Helicobacter pylori glutamate racemase (MurI) showing highly selective anti-H. pylori activity, marked improved solubility, and reduced plasma protein binding. X-ray co-crystal E-I structures were obtained. These uncompetitive inhibitors bind at the MurI dimer interface.
Asunto(s)
Aminas/química , Isomerasas de Aminoácido/química , Química Farmacéutica/métodos , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/enzimología , Animales , Antiinfecciosos/química , Antiinfecciosos/farmacología , Unión Competitiva , Dimerización , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Conformación Molecular , Relación Estructura-ActividadRESUMEN
A novel class of bacterial type-II topoisomerase inhibitor displaying a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold shows potent activity against Gram-positive and fastidious Gram-negative bacteria. Here, we describe a series of N-linked oxazolidinone substituents on the benzisoxazole that improve upon the antibacterial activity of initially described compounds of the class, show favorable PK properties, and demonstrate efficacy in an in vivo Staphylococcus aureus infection model. Inhibition of the topoisomerases DNA gyrase and topoisomerase IV from both Gram-positive and a Gram-negative organisms was demonstrated. Compounds showed a clean in vitro toxicity profile, including no genotoxicity and no bone marrow toxicity at the highest evaluated concentrations or other issues that have been problematic for some fluoroquinolones. Compound 1u was identified for advancement into human clinical trials for treatment of uncomplicated gonorrhea based on a variety of beneficial attributes including the potent activity and the favorable safety profile.
Asunto(s)
Isoxazoles/química , Oxazolidinonas/química , Pirimidinas/farmacología , Inhibidores de Topoisomerasa II/farmacología , Animales , Línea Celular , Cristalografía por Rayos X , Perros , Descubrimiento de Drogas , Humanos , Masculino , Pirimidinas/química , Pirimidinas/toxicidad , Ratas , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/toxicidadRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Barbitúricos/farmacología , Barbitúricos/uso terapéutico , Gonorrea/tratamiento farmacológico , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/uso terapéutico , Adulto , Animales , Antibacterianos/química , Barbitúricos/química , ADN-Topoisomerasas de Tipo II/química , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana , Femenino , Fluoroquinolonas/farmacología , Gonorrea/microbiología , Haplorrinos , Humanos , Isoxazoles , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Modelos Moleculares , Conformación Molecular , Morfolinas , Mutación , Neisseria gonorrhoeae/efectos de los fármacos , Neisseria gonorrhoeae/genética , Oxazolidinonas , Ratas , Compuestos de Espiro/química , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Inhibidores de Topoisomerasa II/química , Adulto JovenRESUMEN
The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (-)-1 in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing in the rat suggested that a high therapeutic margin could be achieved. Importantly, (-)-1 was not cross-resistant with other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin antibacterials. Hence, this class shows considerable promise for the treatment of infections caused by multidrug resistant bacteria, including S. aureus.