期刊
RSC MEDICINAL CHEMISTRY
卷 11, 期 9, 页码 1032-1040出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d0md00145g
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资金
- Swiss National Science Foundation (SNF), NCCR TransCure
- SNF Sinergia grants [CRSII5_180326, CRSII3_160782]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/19311-6, 2017/00689-0]
- Swiss Excellence Scholarship for Foreign Students and Scholars [ESKAS - 2017.0670]
- Austrian Science Funds FWF [P33283]
- Swiss National Science Foundation (SNF) [CRSII3_160782] Funding Source: Swiss National Science Foundation (SNF)
- Austrian Science Fund (FWF) [P33283] Funding Source: Austrian Science Fund (FWF)
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.
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