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Issue 9, 2020
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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

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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

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