title: Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.
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 Ca(2+) 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 ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, 40126 Bologna, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Ioan
authors.forename: Alberto
authors.initials: A
authors.lastname: Leoni
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pedemonte
authors.forename: Alessandra
authors.initials: A
authors.lastname: Locatelli
authors.forename: Matteo
authors.initials: M
authors.lastname: Micucci
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D008164:Luminescent Proteins / Q000737:chemistry / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017384:Sequence Deletion
chemical_list: D000959:Antihypertensive Agents; D001426:Bacterial Proteins; D008164:Luminescent Proteins; C093349:cystic fibrosis transmembrane conductance regulator delta F508; C054562:yellow fluorescent protein, Bacteria; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009543:Nifedipine