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Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor
Transient receptor potential vanilloid 6 (TRPV6) is a calcium channel implicated in multifactorial diseases and overexpressed in numerous cancers. We recently reported the phenyl-cyclohexyl-piperazine cis-22a as the first submicromolar TRPV6 inhibitor. This inhibitor showed a seven-fold selectivity...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513592/ https://www.ncbi.nlm.nih.gov/pubmed/33479695 http://dx.doi.org/10.1039/d0md00145g |
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author | Cunha, Micael Rodrigues Bhardwaj, Rajesh Carrel, Aline Lucie Lindinger, Sonja Romanin, Christoph Parise-Filho, Roberto Hediger, Matthias A. Reymond, Jean-Louis |
author_facet | Cunha, Micael Rodrigues Bhardwaj, Rajesh Carrel, Aline Lucie Lindinger, Sonja Romanin, Christoph Parise-Filho, Roberto Hediger, Matthias A. Reymond, Jean-Louis |
author_sort | Cunha, Micael Rodrigues |
collection | PubMed |
description | Transient receptor potential vanilloid 6 (TRPV6) is a calcium channel implicated in multifactorial diseases and overexpressed in numerous cancers. We recently reported the phenyl-cyclohexyl-piperazine cis-22a as the first submicromolar TRPV6 inhibitor. This inhibitor showed a seven-fold selectivity against the closely related calcium channel TRPV5 and no activity on store-operated calcium channels (SOC), but very significant off-target effects and low microsomal stability. Here, we surveyed analogues incorporating structural features of the natural product capsaicin and identified 3OG, a new oxygenated analog with similar potency against TRPV6 (IC(50) = 0.082 ± 0.004 μM) and ion channel selectivity, but with high microsomal stability and very low off-target effects. This natural product-inspired inhibitor does not exhibit any non-specific toxicity effects on various cell lines and is proposed as a new tool compound to test pharmacological inhibition of TRPV6 mediated calcium flux in disease models. |
format | Online Article Text |
id | pubmed-7513592 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-75135922020-10-07 Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor Cunha, Micael Rodrigues Bhardwaj, Rajesh Carrel, Aline Lucie Lindinger, Sonja Romanin, Christoph Parise-Filho, Roberto Hediger, Matthias A. Reymond, Jean-Louis RSC Med Chem Chemistry Transient receptor potential vanilloid 6 (TRPV6) is a calcium channel implicated in multifactorial diseases and overexpressed in numerous cancers. We recently reported the phenyl-cyclohexyl-piperazine cis-22a as the first submicromolar TRPV6 inhibitor. This inhibitor showed a seven-fold selectivity against the closely related calcium channel TRPV5 and no activity on store-operated calcium channels (SOC), but very significant off-target effects and low microsomal stability. Here, we surveyed analogues incorporating structural features of the natural product capsaicin and identified 3OG, a new oxygenated analog with similar potency against TRPV6 (IC(50) = 0.082 ± 0.004 μM) and ion channel selectivity, but with high microsomal stability and very low off-target effects. This natural product-inspired inhibitor does not exhibit any non-specific toxicity effects on various cell lines and is proposed as a new tool compound to test pharmacological inhibition of TRPV6 mediated calcium flux in disease models. Royal Society of Chemistry 2020-07-16 /pmc/articles/PMC7513592/ /pubmed/33479695 http://dx.doi.org/10.1039/d0md00145g Text en This journal is © The Royal Society of Chemistry 2020 http://creativecommons.org/licenses/by/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0) |
spellingShingle | Chemistry Cunha, Micael Rodrigues Bhardwaj, Rajesh Carrel, Aline Lucie Lindinger, Sonja Romanin, Christoph Parise-Filho, Roberto Hediger, Matthias A. Reymond, Jean-Louis Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor |
title | Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor
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title_full | Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor
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title_fullStr | Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor
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title_full_unstemmed | Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor
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title_short | Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor
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title_sort | natural product inspired optimization of a selective trpv6 calcium channel inhibitor |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513592/ https://www.ncbi.nlm.nih.gov/pubmed/33479695 http://dx.doi.org/10.1039/d0md00145g |
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