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.
