Discovery of (alpha)-aminoazaheterocycle-methlyglyoxal adducts as a new class of high-affinity inhibitors of cystic fibrosis transmembrane conductance regulator chloride channels

Routaboul, Christelle;Norez, Caroline;Melin, Patricia;Molina , MC;Robert, Renaud;et.al.
(2007) The Journal of Pharmacology and Experimental Therapeutics — Vol. 322, n° 1, p. 1023-1035 (2007)

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  • Routaboul, Christelleuniversité de Grenoble
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  • Norez, CarolineUniversité de Poitiers
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  • Melin, PatriciaUniversité de Poitiers
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  • Molina , MCUniversité de Grenoble
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  • Noël, SabrinaUCLouvain
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  • Robert, RenaudUniversité de Poitiers
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  • et. al.
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Abstract
(en) The cystic fibrosis transmembrane conductance regulator (CFTR) represents the main Cl(-) channel in the apical membrane of epithelial cells for cAMP-dependent Cl(-) secretion. Here we report on the synthesis and screening of a small library of nontoxic alpha-aminoazaheterocycle-methylglyoxal adducts, inhibitors of wild-type (WT) CFTR and G551D-, G1349D-, and F508del-CFTR Cl(-) channels. In whole-cell patch-clamp experiments of Chinese hamster ovary (CHO) cells expressing WT-CFTR, we recorded rapid and reversible inhibition of forskolin-activated CFTR currents in the presence of the adducts 5a and 8a,b at 10 pM concentrations. Using iodide efflux experiments, we compared concentration-dependent inhibition of CFTR with glibenclamide (IC(50) = 14.7 microM), 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl-)methylene]-2-thioxo-4-thiazolidinone (CFTR(inh)-172) (IC(50) = 1.2 microM), and alpha-aminoazaheterocycle-methylglyoxal adducts and identified compounds 5a (IC(50) = 71 pM), 8a,b (IC(50) = 2.5 nM), and 7a,b (IC(50) = 3.4 nM) as the most potent inhibitors of WT-CFTR channels. Similar ranges of inhibition were also found when these compounds were evaluated on CFTR channels with the cystic fibrosis mutations F508del (in temperature-corrected human airway epithelial F508del/F508del CF15 cells)-, G551D-, and G1349D-CFTR (expressed in CHO and COS-7 cells). No effect of compound 5a was detected on the volume-regulated or calcium-regulated iodide efflux. Picomolar inhibition of WT-CFTR with adduct 5a was also found using a 6-methoxy-N-(3-sulfopropyl)-quinolinium fluorescent probe applied to the human tracheobronchial epithelial cell line 16HBE14o-. Finally, we found comparable inhibition by 5a or by CFTR(inh)-172 of forskolin-dependent short-circuit currents in mouse colon. To the best of our knowledge, these new nontoxic alpha-aminoazaheterocycle-methylglyoxal adducts represent the most potent compounds reported to inhibit CFTR chloride channels.
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Routaboul, C., Norez, C., Melin, P., Molina, M., Boucherle, B., Bossard, F., Noël, S., Robert, R., & et al. (2007). Discovery of (alpha)-aminoazaheterocycle-methlyglyoxal adducts as a new class of high-affinity inhibitors of cystic fibrosis transmembrane conductance regulator chloride channels. The Journal of Pharmacology and Experimental Therapeutics, 322(1), 1023-1035. https://doi.org/10.1124/jpet.107.123307 (Original work published 2007)