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Issue 9, 2020

Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor

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Abstract

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 (IC50 = 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.

Graphical abstract: Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor

Supplementary files

Article information


Submitted
04 May 2020
Accepted
18 Jun 2020
First published
16 Jul 2020

This article is Open Access

RSC Med. Chem., 2020,11, 1032-1040
Article type
Research Article

Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor

M. R. Cunha, R. Bhardwaj, A. L. Carrel, S. Lindinger, C. Romanin, R. Parise-Filho, M. A. Hediger and J. Reymond, RSC Med. Chem., 2020, 11, 1032 DOI: 10.1039/D0MD00145G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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