Potent s-cis-locked bithiazole correctors of ΔF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy

Jun Yu Gui, Choong L. Yoo, Baoxue Yang, Michael W. Lodewyk, Liping Meng, Tamer T. El-Idreesy, James C. Fettinger, Dean J. Tantillo, A. S. Verkman, Mark J. Kurth

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

N-(5-(2-(5-Chloro-2-methoxyphenylamino)thiazol-4-yl)-4-methylthiazol-2-yl) pivalamide 1 (compound 15Jf) was found previously to correct defective cellular processing of the cystic fibrosis protein ΔF508-CFTR. Eight C4′-C5 C,C-bond-controlling bithiazole analogues of 1 were designed, synthesized, and evaluated to establish that constraining rotation about the bithiazole-tethering has a significant effect on corrector activity. For example, constraining the C4′-C5 bithiazole tether in the s-cis conformation [N-(2-(5-chloro-2- methoxyphenylamino)-7,8-dihydro-6H-cyclohepta[1,2-d:3,4-d′] bithiazole-2′-yl)pivalamide, 29] results in improved corrector activity. Heteroatom placement in the bithaizole core is also critical as evidenced by the decisive loss of corrector activity with s-cis constrained N-(2-(5-chloro-2- methoxyphenylamino)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d′] bithiazole-2′-yl)pivalamide 33. In addition, computational models were utilized to examine the conformational preferences for select model systems. Following our analysis, the "s-cis-locked" cycloheptathiazolothiazole 29 was found to be the most potent bithiazole corrector, with an IC50 of ∼450 nM.

Original languageEnglish (US)
Pages (from-to)6044-6054
Number of pages11
JournalJournal of Medicinal Chemistry
Volume51
Issue number19
DOIs
StatePublished - Oct 9 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Gui, J. Y., Yoo, C. L., Yang, B., Lodewyk, M. W., Meng, L., El-Idreesy, T. T., Fettinger, J. C., Tantillo, D. J., Verkman, A. S., & Kurth, M. J. (2008). Potent s-cis-locked bithiazole correctors of ΔF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy. Journal of Medicinal Chemistry, 51(19), 6044-6054. https://doi.org/10.1021/jm800533c