PG01

PG01 is a potent CFTR Cl^- channel potentiator. PG01 can correct gating defects of CFTR mutants, is effective on b>E193K, G970R and G551D (CFTR mutants) with K_d values of 0.22 μM, 0.45 μM and 1.94 μM, respectively. PG01 is also effective on ΔF508 (K_a of 0.3 μM). PG01 increases ΔF508-CFTR Cl^- current after adding Forskolin^[1][2]. IC50 & Target: CFTR^[1] In Vitro: PG01 itself does not activate F508-CFTR, produces substantial F508-CFTR Cl^- current after the addition of 0.5 and 2 μM Forskolin. PG01 at 100 nM strongly stimulates channel activity with multiple channel openings observed. The apparent K_d for PG01 for G551D-CFTR activation is 1 μM, approximately 100-fold better than that of genistein. The potency for activation G1349D-CFTR by PG01 is even better at 40 nM. PG01 produces large currents in both G551D- and G1349D-CFTR expressing cells. The currents are sensitive to CFTRinh-172 and are not seen in nontransfected cells^[1]. In Vivo: Pharmacokinetic analysis of PG01 in rats is done by serial measurements of plasma concentrations after single bolus infusions (5 mg/kg). PG01 pharmacokinetics fitted a two-compartment model with half-times of ＜5 min and 130 min with volume of distribution 4 L. Microsome metabolism studies and rat pharmacokinetic analysis suggests significantly more rapid metabolism of PG01 than SF-03^[1].