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Beschreibung

A cell-permeable, orally bioavailable dihydroquinoline-carboxamide compound that acts as a potentiator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by directly binding to WT and G551D mutant forms in an allosteric and reversible manner (~ 10 microM) and increases the open probability to restore lung function. Enhances cAMP/PKA-signaling mediated gating activity of both WT and G551D mutants and its potentiation activity is dependent upon the phosphorylated status of CFTR. Does not compete for binding to the canonical ATP-binding catalytic site, but the rate of flux through CFTR increase by 1.5 to 2 fold when ATP concentrations are increased. Shown to increase Cl- secretion by about 10 fold in cultured human CF bronchial epethelia (HBE) carrying G551D/F508del mutations and increases forskolin-stimulated transepethial current (IT, EC50 = 236 nM) far more effectively than genistein (EC50 = 16 microM). Displays favorable pharmacokinetic properties with t1/2= 12 h.Please note that the molecular weight for this compound is batch-specific due to variable water content., A cell-permeable, orally bioavailable dihydroquinoline-carboxamide compound that acts as a potentiator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by directly binding to WT and G551D mutant forms in an allosteric and reversible manner (~ 10 microM) and increases the open probability to restore lung function. Enhances cAMP/PKA-signaling mediated gating activity of both WT and G551D mutants and its potentiation activity is dependent upon the phosphorylated status of CFTR. Does not compete for binding to the canonical ATP-binding catalytic site, but the rate of flux through CFTR increase by 1.5 to 2 fold when ATP concentrations are increased. Shown to increase Cl- secretion by about 10 fold in cultured human CF bronchial epethelia (HBE) carrying G551D/F508del mutations and increases forskolin-stimulated transepethial current (IT, EC50 = 236 nM) far more effectively than genistein (EC50 = 16 microM). Displays favorable pharmacokinetic properties with t1/2= 12 h.