Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in Δf508 cystic fibrosis transmembrane conductance regulator protein

John M. Knapp, Alex B. Wood, Puay Wah Phuan, Michael W. Lodewyk, Dean J. Tantillo, A. S. Verkman, Mark J. Kurth

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing ΔF508-CFTR targeting) and potentiator ("Po", normalizing ΔF508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search - force-field lowest energy assessment - geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct π-stacking conformations to elicit corrector and potentiator activities.

Original languageEnglish (US)
Pages (from-to)1242-1251
Number of pages10
JournalJournal of Medicinal Chemistry
Volume55
Issue number3
DOIs
StatePublished - Feb 9 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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