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Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-07-16 , DOI: 10.1039/d0md00145g Micael Rodrigues Cunha 1, 2 , Rajesh Bhardwaj 3 , Aline Lucie Carrel 1 , Sonja Lindinger 4 , Christoph Romanin 4 , Roberto Parise-Filho 2 , Matthias A Hediger 3 , Jean-Louis Reymond 1
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-07-16 , DOI: 10.1039/d0md00145g Micael Rodrigues Cunha 1, 2 , Rajesh Bhardwaj 3 , Aline Lucie Carrel 1 , Sonja Lindinger 4 , Christoph Romanin 4 , Roberto Parise-Filho 2 , Matthias A Hediger 3 , Jean-Louis Reymond 1
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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.
中文翻译：
天然产物启发选择性 TRPV6 钙通道抑制剂的优化
瞬时受体电位香草酸 6 (TRPV6) 是一种钙通道，与多因素疾病有关，并在多种癌症中过度表达。我们最近报道了苯基环己基哌嗪cis - 22a作为第一个亚微摩尔TRPV6抑制剂。该抑制剂对密切相关的钙通道 TRPV5 显示出七倍的选择性，并且对钙池操纵的钙通道 (SOC) 无活性，但具有非常显着的脱靶效应和较低的微粒体稳定性。在这里，我们调查了包含天然产物辣椒素结构特征的类似物，并鉴定了 3OG，这是一种新的含氧类似物，具有类似的 TRPV6 效力 (IC 50 = 0.082 ± 0.004 μM) 和离子通道选择性，但具有较高的微粒体稳定性和非常低的脱氢酶活性。目标效应。这种天然产物抑制剂不会对各种细胞系表现出任何非特异性毒性作用，并被提议作为一种新的工具化合物来测试疾病模型中 TRPV6 介导的钙流的药理学抑制。
更新日期：2020-09-23
中文翻译：
天然产物启发选择性 TRPV6 钙通道抑制剂的优化
瞬时受体电位香草酸 6 (TRPV6) 是一种钙通道，与多因素疾病有关，并在多种癌症中过度表达。我们最近报道了苯基环己基哌嗪cis - 22a作为第一个亚微摩尔TRPV6抑制剂。该抑制剂对密切相关的钙通道 TRPV5 显示出七倍的选择性，并且对钙池操纵的钙通道 (SOC) 无活性，但具有非常显着的脱靶效应和较低的微粒体稳定性。在这里，我们调查了包含天然产物辣椒素结构特征的类似物，并鉴定了 3OG，这是一种新的含氧类似物，具有类似的 TRPV6 效力 (IC 50 = 0.082 ± 0.004 μM) 和离子通道选择性，但具有较高的微粒体稳定性和非常低的脱氢酶活性。目标效应。这种天然产物抑制剂不会对各种细胞系表现出任何非特异性毒性作用，并被提议作为一种新的工具化合物来测试疾病模型中 TRPV6 介导的钙流的药理学抑制。
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