Discovery and SAR of 4-aminopyrrolidine-2-carboxylic acid correctors of CFTR for the treatment of cystic fibrosis. (15th September 2022)

• Record Type: Journal Article
• Authors: Scanio, Marc J.C.; Searle, Xenia B.; Liu, Bo; Koenig, John R.; Altenbach, Robert J.; Gfesser, Gregory A.; Bogdan, Andrew; Greszler, Stephen; Zhao, Gang; Singh, Ashvani; Fan, Yihong; Swensen, Andrew M.; Vortherms, Timothy; Manelli, Arlene; Balut, Corina; Gao, Wenqing; Yong, Hong; Schrimpf, Michael; Tse, Chris; Kym, Philip; Wang, Xueqing
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 72(2022)
• Publication Date: 2022-09-15
• Subjects: CF cystic fibrosis -- CFTR cystic fibrosis transmembrane conductance regulator protein -- CSE-HRP cell surface expression- horseradish peroxidase -- CYP3A4 cytochrome P450 3A4 -- DCM dichloromethane -- DDI drug-drug interaction -- DMF dimethylformamide -- DMSO dimethyl sulfoxide -- E-Phys electrophysiology -- Emax maximum percent activity -- ER endoplasmic reticulum -- FEV1 forced expiratory volume in 1 s -- Fsp3 sp3 hybridized carbons -- HBE human bronchial epithelial -- HBE-TECC human bronchial epithelial-trans-epithelial current clamp -- HRP horseradish peroxidase -- HTS high throughput screens -- IEQ equivalent CFTR current -- PK pharmacokinetic -- SAR structure activity relationship -- SFC supercritical fluid chromatography -- TEA triethylamine -- TECC transepithelial current clamp -- THF tetrahydrofuran -- WT-CFTR wild-type CFTR; Cystic Fibrosis (CF) -- Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128843
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF.