RESUMEN
High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.
Asunto(s)
Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Hidrocortisona/química , Microsomas/metabolismo , Ratas , Receptores de Glucocorticoides/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
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.
Asunto(s)
Catepsina K/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Nitrilos/síntesis química , Nitrilos/farmacología , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Diseño de Fármacos , Descubrimiento de Drogas , Indicadores y Reactivos , Modelos Moleculares , Curva ROC , Relación Estructura-Actividad , Torsades de Pointes/tratamiento farmacológicoRESUMEN
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
A novel dioxo-triazine series of cathepsin K inhibitors was identified from HTS. A rapid exploratory programme led to the discovery of potent and selective cathepsin K inhibitors, typified by compound 24 which displayed IC(50) values of 17nM against catK and >10,000nM in catL, catB and catS assays.
