RESUMEN
A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.
Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Camptotecina/farmacología , Carbazoles/síntesis química , Glucósidos/síntesis química , Indoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carbazoles/química , Carbazoles/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Glucósidos/química , Glucósidos/farmacología , Humanos , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Irinotecán , Ratones , Microsomas Hepáticos/metabolismo , Inhibidores de Topoisomerasa I , Trasplante HeterólogoRESUMEN
A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Glucósidos/síntesis química , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carbazoles/química , Carbazoles/farmacología , Glucósidos/química , Glucósidos/farmacología , Masculino , Ratones , Trasplante de Neoplasias , Solubilidad , Relación Estructura-Actividad , Agua , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.