RESUMO
Cyano pyrimidine acetylene and cyano pyrimidine t-amine, which belong to a new chemical class, were prepared and tested for inhibitory activities against cathepsin K and the highly homologous cathepsins L and S. The use of novel chemotypes in the development of cathepsin K inhibitors has been demonstrated by derivatives of compounds 1 and 8.
Assuntos
Catepsinas/antagonistas & inibidores , Catepsinas/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Sítios de Ligação , Catepsina K , Catepsina L , Catepsinas/química , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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
Starting from the purine lead structure 1, a new series of cathepsin K inhibitors based on a pyrimidine scaffold have been explored. Investigations of P3 and P2 substituents based on molecular modeling suggestions resulted in potent cathepsin K inhibitors with an improved selectivity profile over other cathepsins.
Assuntos
Catepsinas/antagonistas & inibidores , Catepsinas/química , Cisteína Endopeptidases/química , Modelos Moleculares , Nitrilas/síntese química , Inibidores de Proteases/síntese química , Pirimidinas/síntese química , Animais , Sítios de Ligação , Catepsina K , Cristalografia por Raios X , Nitrilas/química , Nitrilas/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.
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
Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.
Assuntos
Analgésicos/uso terapêutico , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Inibidores de Cisteína Proteinase/administração & dosagem , Inibidores de Cisteína Proteinase/farmacocinética , Doenças do Sistema Nervoso Periférico/enzimologia , RatosRESUMO
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.