RESUMO
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.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacocinética , Animais , Medula Óssea/metabolismo , Catepsina K , Colágeno Tipo I/metabolismo , Haplorrinos , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Ratos , Compostos de Espiro , Distribuição TecidualRESUMO
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.
Assuntos
Catepsinas/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Catepsina K , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirimidinas/química , Pirróis/química , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
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.
