RESUMEN
Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pk(a) of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pk(a) 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrógeno/química , Inhibidores de Proteasas/química , Piridinas/química , Animales , Catepsinas/metabolismo , Ratones , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.
Asunto(s)
Compuestos de Anilina/síntesis química , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Amidas/síntesis química , Amidas/farmacología , Compuestos de Anilina/farmacología , Animales , Inhibidores de Cisteína Proteinasa/farmacología , Flúor , Humanos , Cetonas , Relación Estructura-ActividadRESUMEN
Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.