RESUMEN
On the basis of the pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.
Asunto(s)
Resorción Ósea/tratamiento farmacológico , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Animales , Médula Ósea/metabolismo , Catepsina K , Colágeno Tipo I/metabolismo , Haplorrinos , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Ratas , Compuestos de Espiro , Distribución TisularRESUMEN
Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Catepsina K , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Pirimidinas/química , Pirroles/química , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
A series of 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized as focal adhesion kinase (FAK) inhibitors using molecular modeling in conjunction with a co-crystal structure. Chemistry was developed to introduce functionality onto the 9-aryl ring, which resulted in the identification of potent FAK inhibitors. In particular, compound 32 possessed single-digit nanomolar IC(50) and represents one of the most potent FAK inhibitors discovered to date.