Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids as calcium activated chloride channel inhibitors

Satish Kumar, Wan Namkung, A. S. Verkman, Pawan K. Sharma

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Transmembrane protein 16A (TMEM16A) channels are recently discovered membrane proteins that functions as a calcium activated chloride channel (CaCC). CaCCs are major regulators of various physiological processes, such as sensory transduction, epithelial secretion, smooth muscle contraction and oocyte fertilization. Thirty novel 5-substituted benzyloxy-2-arylbenzofuran-3- carboxylic acids (B01-B30) were synthesized and evaluated for their TMEM16A inhibitory activity by using short circuit current measurements in Fischer rat thyroid (FRT) cells expressing human TMEM16A. IC 50 values were calculated using YFP fluorescence plate reader assay. Final compounds, having free carboxylic group displayed significant inhibition. Eight of the novel compounds B02, B13, B21, B23, B25, B27, B28, B29 exhibit excellent CaCCs inhibition with IC 50 value <6 μM, with compound B25 exhibiting the lowest IC 50 value of 2.8 ± 1.3 μM. None of the tested ester analogs of final benzofuran derivatives displayed TMEM16A/CaCCs inhibition.

Original languageEnglish
Pages (from-to)4237-4244
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number14
DOIs
Publication statusPublished - 2012 Jul 15

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Chloride Channels
Carboxylic Acids
Physiological Phenomena
Proteins
Inbred F344 Rats
Electric current measurement
Muscle Contraction
Fertilization
Short circuit currents
Oocytes
Smooth Muscle
Muscle
Rats
Assays
Thyroid Gland
Membrane Proteins
Esters
Fluorescence
Cells
Derivatives

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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abstract = "Transmembrane protein 16A (TMEM16A) channels are recently discovered membrane proteins that functions as a calcium activated chloride channel (CaCC). CaCCs are major regulators of various physiological processes, such as sensory transduction, epithelial secretion, smooth muscle contraction and oocyte fertilization. Thirty novel 5-substituted benzyloxy-2-arylbenzofuran-3- carboxylic acids (B01-B30) were synthesized and evaluated for their TMEM16A inhibitory activity by using short circuit current measurements in Fischer rat thyroid (FRT) cells expressing human TMEM16A. IC 50 values were calculated using YFP fluorescence plate reader assay. Final compounds, having free carboxylic group displayed significant inhibition. Eight of the novel compounds B02, B13, B21, B23, B25, B27, B28, B29 exhibit excellent CaCCs inhibition with IC 50 value <6 μM, with compound B25 exhibiting the lowest IC 50 value of 2.8 ± 1.3 μM. None of the tested ester analogs of final benzofuran derivatives displayed TMEM16A/CaCCs inhibition.",
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Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids as calcium activated chloride channel inhibitors. / Kumar, Satish; Namkung, Wan; Verkman, A. S.; Sharma, Pawan K.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 14, 15.07.2012, p. 4237-4244.

Research output: Contribution to journalArticle

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