RESUMO
We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.
Assuntos
Catepsinas/antagonistas & inibidores , Química Farmacêutica/métodos , Inibidores de Cisteína Proteinase/síntese química , Nitrilas/síntese química , Peptídeos/química , Pirimidinas/química , Pirimidinas/síntese química , Animais , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Masculino , Conformação Molecular , Nitrilas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.
Assuntos
Catepsinas/antagonistas & inibidores , Cisteína Endopeptidases/síntese química , Inibidores de Cisteína Proteinase/síntese química , Disponibilidade Biológica , Catepsina K , Catepsina L , Catepsinas/química , Química Farmacêutica , Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.
Assuntos
Catepsinas/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Catepsina L , Técnicas de Química Combinatória , Cisteína Endopeptidases , Humanos , Masculino , Estrutura Molecular , Esclerose Múltipla/tratamento farmacológico , Dor/tratamento farmacológico , Pirimidinas/sangue , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.