Bai Sha, Nagai Masazumi, Koerner Steffi K, Veves Aristidis, Sun Lijun
Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
The Rongxiang Xu, MD Center for Regenerative Therapeutics, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Bioorg Med Chem Lett. 2017 Feb 1;27(3):393-397. doi: 10.1016/j.bmcl.2016.12.062. Epub 2016 Dec 27.
Aberrant activation of mast cells contributes to the development of numerous diseases including cancer, autoimmune disorders, as well as diabetes and its complications. The influx of extracellular calcium via the highly calcium selective calcium-release activated calcium (CRAC) channel controls mast cell functions. Intracellular calcium homeostasis in mast cells can be maintained via the modulation of the CRAC channel, representing a critical point for therapeutic interventions. We describe the structure-activity relationship study (SAR) of indazole-3-carboxamides as potent CRAC channel blockers and their ability to stabilize mast cells. Our SAR results show that the unique regiochemistry of the amide linker is critical for the inhibition of calcium influx, the release of the pro-inflammatory mediators β-hexosaminidase and tumor necrosis factor α by activated mast cells. Thus, the indazole-3-carboxamide 12d actively inhibits calcium influx and stabilizes mast cells with sub-μM IC. In contrast, its reverse amide isomer 9c is inactive in the calcium influx assay even at 100μM concentration. This requirement of the specific 3-carboxamide regiochemistry in indazoles is unprecedented in known CRAC channel blockers. The new structural scaffolds described in this report expand the structural diversity of the CRAC channel blockers and may lead to the discovery of novel immune modulators for the treatment of human diseases.
肥大细胞的异常激活会导致包括癌症、自身免疫性疾病以及糖尿病及其并发症在内的多种疾病的发生。细胞外钙通过高度钙选择性的钙释放激活钙（CRAC）通道内流，控制肥大细胞的功能。肥大细胞内的钙稳态可通过调节CRAC通道来维持，这是治疗干预的关键点。我们描述了吲唑-3-甲酰胺作为有效的CRAC通道阻滞剂的构效关系研究（SAR）及其稳定肥大细胞的能力。我们的SAR结果表明，酰胺连接子独特的区域化学结构对于抑制钙内流、活化肥大细胞释放促炎介质β-己糖胺酶和肿瘤坏死因子α至关重要。因此，吲唑-3-甲酰胺12d能有效抑制钙内流，以亚微摩尔的半数抑制浓度（IC）稳定肥大细胞。相比之下，其反向酰胺异构体9c即使在100μM浓度下，在钙内流测定中也无活性。吲唑中特定3-甲酰胺区域化学结构的这种要求在已知的CRAC通道阻滞剂中是前所未有的。本报告中描述的新结构支架扩展了CRAC通道阻滞剂的结构多样性，并可能导致发现用于治疗人类疾病的新型免疫调节剂。
