RESUMEN
Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B.
Asunto(s)
Amidas/química , Antivirales/síntesis química , Inhibidores Enzimáticos/síntesis química , Hepacivirus/efectos de los fármacos , Tiofenos/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacología , Antivirales/química , Antivirales/farmacología , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Proteínas no Estructurales Virales/metabolismoRESUMEN
Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5â³, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.
Asunto(s)
Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridonas/química , Piridonas/farmacología , Receptores Purinérgicos P2X7/metabolismo , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Halogenación , HumanosRESUMEN
The metabolic fate of three aromatic carboxylic acid analogs under evaluation as prostaglandin I2-preferring receptor antagonists was studied. The initial analog with unsubstituted phenyl groups was subject to a complex set of aromatic oxidative biotransformations. By introduction of one or two fluorines, these pathways were inhibited. All three analogs were metabolized to a wide variety of carboxylic acid conjugates. Among these were several conjugates formed via secondary metabolism and oxidation of acyl glutathione intermediates. Two of the structure classes, represented by the S-methyl-N-cysteinylglycine conjugate and the N-cysteinylglycine disulfide conjugates, have been described only rarely in the literature. The related S-oxide of the S-methyl-N-cysteinylglycine conjugate and the N,S-bis-acyl derivative of cysteinylglycine are here described for the first time as conjugate metabolites of carboxylic drugs.