RESUMEN

We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen.

Asunto(s)

Agonistas de los Canales de Cloruro/química , Agonistas de los Canales de Cloruro/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/agonistas , Indoles/química , Indoles/farmacología , Aminofenoles/farmacología , Animales , Línea Celular , Agonistas de los Canales de Cloruro/síntesis química , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Humanos , Indoles/síntesis química , Modelos Moleculares , Mutación , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Quinolonas/farmacología , Ratas , Relación Estructura-Actividad