Abstract : After the discovery of a new stereoselective reaction between methylglyoxal and α-aminoazaheterocycles in water under mild conditions leading to a new family of compounds (family I), some of the resulting compounds appeared to be able to modulate efficiently the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Mutations of this protein which forms a cAMP-regulated chloride channel cause the severe genetic disease cystic fibrosis.
Small molecules able to modulate Cl– channels are interesting to understand the physiological role of these channels and also in the development of molecules of therapeutic interest. In the search for the chemical structure of the pharmacophore responsible for the observed effects in the active compounds (a positively charged nitrogen atom linked through two carbon atoms to a negatively charged oxygen atom), various compounds carrying or not the assumed pharmacophore were prepared and evaluated (compounds of families II and III prepared from compounds of the family I). Some of the prepared compounds were found to be interesting modulators of CFTR channels confirming the proposed structure of the pharmacophore.