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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor

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Author(s):
Cunha, Micael Rodrigues [1, 2] ; Bhardwaj, Rajesh [3] ; Carrel, Aline Lucie [1] ; Lindinger, Sonja [4] ; Romanin, Christoph [4] ; Parise-Filho, Roberto [2] ; Hediger, Matthias A. [3] ; Reymond, Jean-Louis [1]
Total Authors: 8
Affiliation:
[1] Univ Bern, Dept Chem & Biochem, Freiestr 3, CH-3012 Bern - Switzerland
[2] Univ Sao Paulo, Dept Pharm, Prof Lineu Prestes Ave 580, BR-05508000 Sao Paulo - Brazil
[3] Inselspital Bern, Univ Hosp Bern, Dept Hypertens & Nephrol, CH-3010 Bern - Switzerland
[4] Johannes Kepler Univ Linz, Inst Biophys, Gruberstr 40, A-4020 Linz - Austria
Total Affiliations: 4
Document type: Journal article
Source: RSC MEDICINAL CHEMISTRY; v. 11, n. 9, p. 1032-1040, SEP 1 2020.
Web of Science Citations: 1
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-piperazinecis-22aas 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 mu M) 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. (AU)

FAPESP's process: 13/19311-6 - Design, synthesis and antitumor activity of aryl-sulfonylhydrazone compounds
Grantee:Thais Batista Fernandes
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 17/00689-0 - New antineoplastic agents: synthesis, molecular docking and antitumoral activity of capsaicinoids analogues
Grantee:Roberto Parise Filho
Support Opportunities: Regular Research Grants