RESUMO
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
Assuntos
Amidas , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase , Cetonas , Pirrolidinas , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Sítios de Ligação , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacocinética , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Concentração Inibidora 50 , Cetonas/síntese química , Cetonas/farmacocinética , Cetonas/farmacologia , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Inibidores de Serina Proteinase , Relação Estrutura-AtividadeRESUMO
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Assuntos
Aldeídos/química , Catepsinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Semicarbazonas/farmacologia , Animais , Catepsina K , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Modelos Moleculares , Conformação Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ratos , Semicarbazonas/síntese química , Semicarbazonas/química , Solubilidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Cetonas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Sítios de Ligação , Disponibilidade Biológica , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Catepsina K , Catepsinas/química , Inibidores de Cisteína Proteinase/farmacocinética , Inibidores de Cisteína Proteinase/farmacologia , Modelos Animais de Doenças , Hipocalcemia/tratamento farmacológico , Hipocalcemia/metabolismo , Cetonas/farmacocinética , Cetonas/farmacologia , Ratos , Ratos Wistar , Solubilidade , Relação Estrutura-AtividadeRESUMO
Conversion of the proline-derived cyanamide lead to an acyclic cyanamide capable of forming an additional hydrogen bond with cathepsin K resulted in a large increase in inhibitory activity. An X-ray structure of a co-crystal of a cyanamide with cathepsin K confirmed the enzyme interaction. Furthermore, a representative acyclic cyanamide inhibitor 6r was able to attenuate bone resorption in the rat calvarial model.
Assuntos
Catepsinas/antagonistas & inibidores , Cianamida/química , Inibidores de Cisteína Proteinase/farmacologia , Osteogênese/efeitos dos fármacos , Animais , Sítios de Ligação , Reabsorção Óssea , Catepsina B/antagonistas & inibidores , Catepsina H , Catepsina K , Catepsina L , Cristalografia por Raios X , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/síntese química , Modelos Animais de Doenças , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Starting from a PDE IV inhibitor hit derived from high throughput screening of the compound collection, a key pyrrolidine cyanamide pharmacophore was identified. Modifications of the pyrrolidine ring produced enhancements in cathepsin K inhibition. An X-ray co-crystal structure of a cyanamide with cathepsin K confirmed the mode of inhibition.
Assuntos
Catepsinas/antagonistas & inibidores , Cianamida/química , Inibidores de Cisteína Proteinase/síntese química , Animais , Catepsina K , Cristalografia por Raios X , Ciclização , Inibidores de Cisteína Proteinase/farmacologia , Concentração Inibidora 50 , Pirrolidinas/química , Relação Estrutura-AtividadeRESUMO
A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors.
Assuntos
Amidas/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Sítios de Ligação , Catepsina K , Catepsinas/química , Humanos , Relação Estrutura-AtividadeRESUMO
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130 pM.
Assuntos
Aldeídos/química , Catepsinas/antagonistas & inibidores , Inibidores de Proteases/síntese química , Aldeídos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Carbamatos/química , Catepsina K , Humanos , Concentração Inibidora 50 , Norleucina/química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of reversible ketoamides based inhibitors of cathepsin K have led to identification of potent and selective compounds. Crystallographic studies have given insights into the mode of binding of these inhibitors. A series of ketoamides with varying P1 moieties were first synthesized to find an optimum group that would fit into the S1 subsite of the cysteine protease, cathepsin K. With a desired P1 group in place a variety of heterocyclic analogues in the P' region were synthesized to study their steric and electronic effects. In the process of exploring these P' heterocyclic variations, excellent selectivity was gained over other highly homologous cysteine proteases, including cathepsins L, S, and V. The favorable pharmacokinetic properties of some of these cathepsin K inhibitors in rats make them suitable for evaluation in rodent osteoporosis models. A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model. These inhibitors provide a viable lead series in the discovery of new therapies for the prevention and treatment of osteoporosis
Assuntos
Amidas/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Cetonas/síntese química , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Disponibilidade Biológica , Cálcio/sangue , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/farmacocinética , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Cetonas/farmacocinética , Cetonas/farmacologia , Masculino , Modelos Moleculares , Estrutura Molecular , Osteoporose/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM.