RESUMEN
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Quinolinas/química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Sitios de Unión , Glucemia/metabolismo , Cristalografía por Rayos X , Diabetes Mellitus Experimental/metabolismo , Perros , Transferencia Resonante de Energía de Fluorescencia , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Ligandos , Ratones , Conformación Molecular , Estructura Terciaria de Proteína , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiofenos/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Humanos , Isoxazoles/farmacología , Naftalenos/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Tiofenos/farmacocinéticaRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Asunto(s)
Isoxazoles/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Cristalografía por Rayos X , Transferencia Resonante de Energía de Fluorescencia , Isoxazoles/química , Isoxazoles/farmacología , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-ActividadRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Colestasis/tratamiento farmacológico , Proteínas de Unión al ADN/agonistas , Isoxazoles/síntesis química , Isoxazoles/farmacología , Naftalenos/síntesis química , Naftalenos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Administración Oral , Animales , Ácidos Carboxílicos/química , Colestasis/metabolismo , Colestasis/patología , Cristalografía por Rayos X , Proteínas de Unión al ADN/química , Modelos Animales de Enfermedad , Perros , Mucosa Gástrica/metabolismo , Haplorrinos , Isoxazoles/química , Ratones , Conformación Molecular , Estructura Molecular , Naftalenos/química , Ratas , Receptores Citoplasmáticos y Nucleares/química , Estómago/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/químicaRESUMEN
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Cetonas/química , Cetonas/farmacocinética , Administración Oral , Disponibilidad Biológica , Catepsina K , Catepsinas/química , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/administración & dosificación , Humanos , Cetonas/administración & dosificación , Conformación Proteica , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Aldehídos/química , Catepsinas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Semicarbazonas/farmacología , Animales , Catepsina K , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Modelos Moleculares , Conformación Molecular , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacología , Ratas , Semicarbazonas/síntesis química , Semicarbazonas/química , Solubilidad , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Amidas/síntesis química , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Cetonas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Catepsina K , Catepsinas/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Modelos Animales de Enfermedad , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/metabolismo , Cetonas/farmacocinética , Cetonas/farmacología , Ratas , Ratas Wistar , Solubilidad , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Cianamida/química , Inhibidores de Cisteína Proteinasa/farmacología , Osteogénesis/efectos de los fármacos , Animales , Sitios de Unión , Resorción Ósea , Catepsina B/antagonistas & inhibidores , Catepsina H , Catepsina K , Catepsina L , Cristalografía por Rayos X , Cisteína Endopeptidasas , Inhibidores de Cisteína Proteinasa/síntesis química , Modelos Animales de Enfermedad , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Unión Proteica , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Several novel ketoamide-based inhibitors of cathepsin K have been identified. Starting from a modestly potent inhibitor, structural screening of P2 elements led to 100-fold enhancements in inhibitory activity. Modifications to one of these leads resulted in an orally bioavailable cathepsin K inhibitor.
Asunto(s)
Amidas/farmacología , Catepsinas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Amidas/síntesis química , Amidas/farmacocinética , Sitios de Unión , Disponibilidad Biológica , Catepsina K , Catepsinas/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Cinética , Conformación Proteica , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Cianamida/química , Inhibidores de Cisteína Proteinasa/síntesis química , Animales , Catepsina K , Cristalografía por Rayos X , Ciclización , Inhibidores de Cisteína Proteinasa/farmacología , Concentración 50 Inhibidora , Pirrolidinas/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Aldehídos/química , Catepsinas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Aldehídos/farmacología , Sitios de Unión/efectos de los fármacos , Carbamatos/química , Catepsina K , Humanos , Concentración 50 Inhibidora , Norleucina/química , Inhibidores de Proteasas/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of ketoamide-based inhibitors of cathepsin K has been identified. Modifications to P(2) and P(3) elements were crucial to enhancing inhibitory activity. Although not optimized, a selected inhibitor was effective in attenuating type I collagen hydrolysis in a surrogate assay of bone resorption.
Asunto(s)
Resorción Ósea/metabolismo , Huesos/efectos de los fármacos , Catepsinas/antagonistas & inhibidores , Colágeno Tipo I/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacología , Huesos/patología , Catepsina K , Diseño de Fármacos , Humanos , Hidrólisis , Relación Estructura-ActividadRESUMEN
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.