RESUMEN
The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.
Asunto(s)
Antivirales/farmacología , Péptidos Cíclicos/farmacología , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Antivirales/farmacocinética , Células CHO , Cricetulus , Descubrimiento de Drogas , Estabilidad de Medicamentos , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Estructura Molecular , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/metabolismo , Péptidos Cíclicos/farmacocinética , Ratas , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/metabolismo , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-ActividadRESUMEN
Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.