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EOS789, a novel pan-phosphate transporter inhibitor, is effective for the treatment of chronic kidney disease-mineral bone disorder.

Abstract：

:Chronic kidney disease is characterized as impaired renal function along with the imbalance and dysregulation of mineral metabolism; recognized as chronic kidney disease-mineral and bone disorder. Hyperphosphatemia, characterized by altered phosphate homeostasis along with elevated fibroblast growth factor-23 and intact parathyroid hormone, is such an alteration of mineral metabolism. We discovered a novel inhibitor, EOS789, that interacts with several sodium-dependent phosphate transporters (NaPi-IIb, PiT-1, and PiT-2) known to contribute to intestinal phosphate absorption. This inhibitor dose-dependently increased the fecal phosphorus excretion rate and inversely decreased the urinary phosphorus excretion rate in normal rats, suggesting inhibition of intestinal phosphorus absorption. In rats with adenine-induced hyperphosphatemia, EOS789 markedly decreased the serum phosphate, fibroblast growth factor-23, and intact parathyroid hormone below values found in normal control rats. Notably, this pan-phosphate transporter inhibitor exhibited a more potent effect on serum phosphate than a NaPi-IIb-selective inhibitor in rats with hyperphosphatemia indicating that PiT-1 and PiT-2 play important roles in intestinal phosphate absorption. Moreover, in a long-term study, EOS789 sustained the suppression of serum phosphorus in parallel with fibroblast growth factor-23 and intact parathyroid hormone and ameliorated ectopic calcification of the thoracic aorta. Additionally, EOS789 treatment also ameliorated kidney deterioration in rats with progressive kidney injury, probably due to the strict phosphate control. Thus, EOS789 has potent efficacy against hyperphosphatemia and its complications and could provide a significant benefit to patients who are ineffectively treated with phosphate binders.

journal_name

Kidney Int

journal_title

Kidney international

authors

Tsuboi Y,Ohtomo S,Ichida Y,Hagita H,Ozawa K,Iida M,Nagao S,Ikegami H,Takahashi T,Horiba N

doi

10.1016/j.kint.2020.02.040

subject

Has Abstract

pub_date

2020-08-01 00:00:00

pages

343-354

issue

2

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(20)30406-3

journal_volume

98

pub_type

杂志文章

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