RESUMEN
A series of potent α4ß1/α4ß7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Integrinas/antagonistas & inhibidores , Administración Oral , Animales , Área Bajo la Curva , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Modelos Animales de Enfermedad , Semivida , Humanos , Integrina alfa4beta1/metabolismo , Integrinas/metabolismo , Células Jurkat , Microsomas Hepáticos/metabolismo , RatasRESUMEN
Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.
Asunto(s)
Integrina alfa4/química , Polietilenglicoles/química , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Ésteres , Semivida , Humanos , Inyecciones Subcutáneas , Integrina alfa4/inmunología , Integrina alfa4/metabolismo , Células Jurkat , RatasRESUMEN
The 4-isoxazolyl-dihydropyridines (IDHPs) exhibit inhibition of the multidrug-resistance transporter (MDR-1), and exhibit an SAR distinct from their activity at voltage gated calcium channels (VGCC). Among the four most active IDHPs, three were branched at C-5 of the isoxazole, including the most active analog, 1k.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Dicarbetoxidihidrocolidina/análogos & derivados , Dihidropiridinas/metabolismo , Isoxazoles/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Células CACO-2 , Canales de Calcio/química , Canales de Calcio/metabolismo , Dicarbetoxidihidrocolidina/síntesis química , Dicarbetoxidihidrocolidina/química , Dicarbetoxidihidrocolidina/metabolismo , Dihidropiridinas/química , Humanos , Isoxazoles/síntesis química , Isoxazoles/química , Espectroscopía de Resonancia Magnética , Modelos Químicos , Unión Proteica , Relación Estructura-Actividad , TermodinámicaRESUMEN
In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-ß in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.
Asunto(s)
Aminopiridinas/química , Proteína Quinasa 10 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 9 Activada por Mitógenos/antagonistas & inhibidores , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/química , Inhibidores de Proteínas Quinasas/química , Triazinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapéutico , Animales , Sitios de Unión , Sistema Nervioso Central/metabolismo , Simulación por Computador , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Proteína Quinasa 10 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Triazinas/farmacocinética , Triazinas/uso terapéuticoRESUMEN
Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.
