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 2) 2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG 2) 2-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 2) 2-IP4 disrupts the nucleation and growth of pathological calcification.

In the past decade, significant progress has been made in understanding the medical threats posed by vascular calcification (VC). This recent development comes after a long history of misinterpreting this condition as a mere consequence of aging. As a result, there is presently no pharmacological treatment approved for the prevention or ablation of VC. Patients diagnosed with this chronic and debilitating condition are hence left at a great risk of experiencing serious cardiovascular events. Researchers, however, are ever better understanding the disease's pathophysiology, and promising avenues for drug development have emerged. In this review, recent clinical results of proposed calcification inhibitors are consolidated and selected investigational therapeutics are portrayed. Finally, opportunities for drug development approaches are highlighted and an objective account of challenges that remain in achieving this goal is provided.

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