Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium.
Nat Commun. 2020 Feb 5;11(1):721. doi: 10.1038/s41467-019-14091-4.
Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG)-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG)-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG)-IP4 disrupts the nucleation and growth of pathological calcification.
肌醇六磷酸（IP6）是一种天然产物，已知能抑制血管钙化（VC），但在大剂量静脉注射后其效力有限且在血浆中的暴露量低。在这里，我们报告了一系列肌醇磷酸盐类似物的设计，作为结晶抑制剂，其中 4,6-二-O-（甲氧基二乙二醇基）-肌醇-1,2,3,5-四磷酸酯（OEG）-IP4 在体外显示出增加的活性，并且在皮下注射后具有比 IP6 更有利的药代动力学和安全性特征。（OEG）-IP4 能有效稳定钙磷蛋白颗粒（CPP）的生长，在不同的 VC 体外模型（即人血清、原代细胞培养物和组织外植体）中均表现出低微摩尔的活性，并在很大程度上阻止了 VC 在啮齿动物模型中的发展，而不会引起与血清钙螯合相关的毒性。这些数据表明了一种与 VC 病因无关的作用机制，其中（OEG）-IP4 破坏了病理性钙化的成核和生长。
