RESUMEN
Antagonists of the 5-HT(6) receptor have been shown to improve cognitive function in a wide range of animal models and as such may prove to be attractive agents for the symptomatic treatment of cognitive disorders such as Alzheimer's disease (AD) and schizophrenia. We report herein the identification and SAR around N-(2-aminoalkyl)-1-(arylsulfonyl)indoline-3-carboxamides-a novel chemotype of 5-HT(6) antagonists.
Asunto(s)
Amidas/química , Indoles/química , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/síntesis química , Amidas/farmacología , Animales , Disponibilidad Biológica , Descubrimiento de Drogas , Humanos , Indoles/farmacología , Masculino , Microsomas , Farmacocinética , Ratas , Ratas Wistar , Agonistas de Receptores de Serotonina/química , Relación Estructura-ActividadRESUMEN
Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.
Asunto(s)
Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Pirimidinas/química , Administración Oral , Animales , Sitios de Unión , Catepsina K/metabolismo , Línea Celular , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacocinética , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , 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.