RESUMEN
Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Purinas/química , Dominio Catalítico , Catepsina K/antagonistas & inhibidores , Catepsina K/metabolismo , Catepsinas/metabolismo , Línea Celular , Simulación por Computador , Humanos , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Purinas/síntesis química , Purinas/farmacología , Pirimidinas/químicaRESUMEN
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%.