RESUMEN
Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, we describe the discovery and optimization of a novel potentiator series. Scaffold hopping, focusing on retaining the different intramolecular contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clinical candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.
Asunto(s)
Fibrosis Quística/tratamiento farmacológico , Descubrimiento de Drogas , Piridinas/farmacología , Piridinas/uso terapéutico , Animales , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Humanos , Piridinas/química , Piridinas/farmacocinética , RatasRESUMEN
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described.
Asunto(s)
Agonistas de los Canales de Cloruro/química , Fibrosis Quística/tratamiento farmacológico , Descubrimiento de Drogas , Proteínas Mutantes/efectos de los fármacos , Aminofenoles/farmacocinética , Animales , Agonistas de los Canales de Cloruro/farmacocinética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Humanos , Mutación , Pirazoles/química , Pirazoles/farmacocinética , Quinolonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The catalytic asymmetric 1,2-addition of a series of arylboronic acids to 2,2,2-trifluoroacetophenones is described with high isolated yields (up to 96%) and good enantioselectivities (up to 83% ee) using a rhodium(I)/phosphoramidite catalyst.