RESUMEN
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Asunto(s)
Indoles/química , Indoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Cristalografía por Rayos X , Indazoles/química , Indazoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/química , Fosforilación , Relación Estructura-ActividadRESUMEN
Elaboration of our previously disclosed spiropiperidine template led to the development of a series of novel CCR5 antagonists. Results of SAR exploration and preliminary lead characterization are described.
Asunto(s)
Antagonistas de los Receptores CCR5 , Imidazolidinas/síntesis química , Imidazolidinas/farmacología , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Imidazolidinas/química , Imidazolidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Asunto(s)
Fármacos Anti-VIH/química , Benzamidas/química , Antagonistas de los Receptores CCR5 , Inhibidores de Fusión de VIH/química , Pirroles/química , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Pirroles/síntesis química , Pirroles/farmacocinética , Ratas , Receptores CCR5/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed.
Asunto(s)
Antagonistas de los Receptores CCR5 , Piperidinas/química , Piperidinas/farmacología , Receptores CCR5/metabolismo , Animales , Células CACO-2 , Perros , Haplorrinos , Humanos , Piperidinas/farmacocinética , Ratas , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.