ΔF508-CFTR correctors: synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles.

Abstract

The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry.

• Authors: Long Ye, Bao Hu, Faris El-Badri, Brandi M Hudson, Puay-Wah Phuan, A S Verkman, Dean J Tantillo, Mark J Kurth
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 24 Pg. 5840-5844 (Dec 15 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 25452003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Imidazoles
• Oxadiazoles
• Oxazoles
• Thiadiazoles
• Thiazoles
• cystic fibrosis transmembrane conductance regulator delta F508
• imidazolone
• Water
• Cystic Fibrosis Transmembrane Conductance Regulator

Topics

• Cystic Fibrosis (metabolism, pathology)
• Cystic Fibrosis Transmembrane Conductance Regulator (chemistry, metabolism)
• Humans
• Imidazoles (chemistry, metabolism)
• Kinetics
• Molecular Conformation
• Oxadiazoles (chemistry, metabolism)
• Oxazoles (chemistry, metabolism)
• Protein Binding
• Structure-Activity Relationship
• Thermodynamics
• Thiadiazoles (chemistry, metabolism)
• Thiazoles (chemistry)
• Water (chemistry)