The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca2+ channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants (Mol. Pharmacol. 2005, 68, 1736). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects (J. Med. Chem. 2008, 51, 1592) to enhance the activity of ƒ¢F508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
R. Budriesi, P. Ioan, A. Leoni, N. Pedemonte, A. Locatelli, M. Micucci, et al. (2011). Cystic Fibrosis: a New Target for 4-Imidazo[2,1-b]thiazole-1,4- Dihydropyridines. JOURNAL OF MEDICINAL CHEMISTRY, 54, 3094-3885.
Cystic Fibrosis: a New Target for 4-Imidazo[2,1-b]thiazole-1,4- Dihydropyridines.
BUDRIESI, ROBERTA;IOAN, PIERFRANCO;LEONI, ALBERTO;LOCATELLI, ALESSANDRA;MICUCCI, MATTEO;CHIARINI, ALBERTO;
2011
Abstract
The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca2+ channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants (Mol. Pharmacol. 2005, 68, 1736). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects (J. Med. Chem. 2008, 51, 1592) to enhance the activity of ƒ¢F508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
