CFTR(inh)-172

CFTR(inh)-172 is a potent and selective blocker of the CFTR chloride channel; reversibly inhibits CFTR short-circuit current in less than 2 minutes with a K_i of 300 nM. IC50 & Target: Ki: 300 nM (CFTR)^[1] In Vitro: Inhibition by CFTR(inh)-172 is complete in approximately 10 minutes (t_1/2=4 minutes) and is reversed after ishout with t_1/2 approximately 5 minutes. CFTRinh-172 is nontoxic to FRT cells after 24 hours at concentrations up to 100 μM^[1]. CFTR(inh)-172 does not alter CFTR unitary conductance (8 pS), but reduces open probability by > 90% with K_i=0.6 μM. This effect is due to increased mean channel closed time without changing mean channel open time. The K_i values for inhibition of Cl^- current in wild-type, G551D, and G1349D CFTR are about 0.5 μM; however, K_i is significantly reduced to 0.2 μM for vF508 CFTR^[2]. In Vivo: A single intraperitoneal injection of CFTR(inh)-172 (250 μg/kg) in mice reduces by more than 90% cholera toxin–induced fluid secretion in the small intestine over 6 hours. CFTR(inh)-172 is nontoxic at high concentrations in mouse models. CFTRinh-172 significantly reduces fluid secretion to that in saline control loops, whereas an inactive CFTRinh-172 analog does not inhibit fluid secretion^[1].