Design and synthesis of a hybrid potentiator-corrector agonist of the cystic fibrosis mutant protein DeltaF508-CFTR

• Published in: Bioorganic & medicinal chemistry letters 2010-01, Vol.20 (1), p.87-91
• Main Authors: Mills, Aaron D, Yoo, Choong, Butler, Jeffrey D, Yang, Baoxue, Verkman, A S, Kurth, Mark J
• Format: Article
• Language: English
• Subjects: Cystic Fibrosis - drug therapy; Cystic Fibrosis Transmembrane Conductance Regulator - agonists; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Drug Design; Glycine - analogs & derivatives; Glycine - chemistry; Humans; Ion Channel Gating; Mutation; Protein Folding; Small Molecule Libraries; Structure-Activity Relationship; Thiazoles - chemistry
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2009.11.020

A developing therapy of cystic fibrosis caused by the DeltaF508 mutation in CFTR employs correction of defective CFTR chloride channel gating by a 'potentiator' and of defective CFTR protein folding by a 'corrector'. Based on SAR data for phenylglycine-type potentiators and bithiazole correctors, we designed a hybrid molecule incorporating an enzymatic hydrolysable linker to deliver the potentiator (PG01) fragment 2 and the corrector (Corr-4a) fragment 13. The hybrid molecule 14 contained PG01-OH and Corr-4a-linker-CO(2)H moieties, linked with an ethylene glycol spacer through an ester bond. The potentiator 2 and corrector 13 fragments (after cleavage) had low micromolar potency for restoration of DeltaF508-CFTR channel gating and cellular processing, respectively. Cleavage of hybrid molecule 14 by intestinal enzymes under physiological conditions produced the active potentiator 2 and corrector fragments 13, providing proof-of-concept for small-molecule potentiator-corrector hybrids as a single drug therapy for CF caused by the DeltaF508 mutation.