Pyrazolylthiazole as Δf508-cystic fibrosis transmembrane conductance regulator correctors with improved hydrophilicity compared to bithiazoles

Long Ye, John M. Knapp, Panjamaporn Sangwung, James C. Fettinger, A. S. Verkman, Mark J. Kurth

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Deletion of phenylalanine residue 508 (ΔF508) in the cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR) is a major cause of CF. Small molecule "correctors"of defective ΔF508-CFTR cellular processing hold promise for CF therapy. We previously identified and characterized bithiazole CF corrector 1 and s-cis-locked bithiazole 2. Herewe report the regiodivergent synthesis of Nγ and Nβ isomers of thiazole-tethered pyrazoles with improved hydrophilicity compared to bithiazoles. We synthesized a focused library of 54 pyrazolylthiazoles 3, which included examples of both regioisomers 4 and 5. The thiazole-tethered pyrazoles allowed incorporation of property-modulating functionality on the pyrazole ring (ester, acid, and amide) while retaining ΔF508-CFTR corrector activity (EC50) of under 1 μM. The most active pyrazolylthiazole (14h) has an experimentally determined log P of 4.1, which is 1.2 log units lower than bithiazole CF corrector 1.

Original languageEnglish (US)
Pages (from-to)3772-3781
Number of pages10
JournalJournal of Medicinal Chemistry
Volume53
Issue number9
DOIs
StatePublished - May 13 2010

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Cystic Fibrosis Transmembrane Conductance Regulator
Hydrophobic and Hydrophilic Interactions
Cystic Fibrosis
Pyrazoles
Thiazoles
Proteins
Phenylalanine
Amides
Libraries
Esters
Acids
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Pyrazolylthiazole as Δf508-cystic fibrosis transmembrane conductance regulator correctors with improved hydrophilicity compared to bithiazoles. / Ye, Long; Knapp, John M.; Sangwung, Panjamaporn; Fettinger, James C.; Verkman, A. S.; Kurth, Mark J.

In: Journal of Medicinal Chemistry, Vol. 53, No. 9, 13.05.2010, p. 3772-3781.

Research output: Contribution to journalArticle

Ye, Long ; Knapp, John M. ; Sangwung, Panjamaporn ; Fettinger, James C. ; Verkman, A. S. ; Kurth, Mark J. / Pyrazolylthiazole as Δf508-cystic fibrosis transmembrane conductance regulator correctors with improved hydrophilicity compared to bithiazoles. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 9. pp. 3772-3781.
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