RESUMEN
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Cetonas/química , Cetonas/farmacocinética , Administración Oral , Disponibilidad Biológica , Catepsina K , Catepsinas/química , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/administración & dosificación , Humanos , Cetonas/administración & dosificación , Conformación Proteica , Relación Estructura-ActividadRESUMEN
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
Asunto(s)
Amidas/síntesis química , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Cetonas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Catepsina K , Catepsinas/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Modelos Animales de Enfermedad , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/metabolismo , Cetonas/farmacocinética , Cetonas/farmacología , Ratas , Ratas Wistar , Solubilidad , Relación Estructura-ActividadRESUMEN
An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P1 and P1' elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors.