Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 9, Issue 5, Pages 440-445Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00013
Keywords
SLC34A1; NaPi2a; sodium phosphate cotransporter; kidney; proximal tubule; SLC
Categories
Funding
- NIH [DK11794, DK46718]
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Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary phosphate excretion and correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease-mineral and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. Herein, we detail the discovery of the first series of selective NaPi2a inhibitors, resulting from optimization of a high-throughput screening hit. The oral PK profile of inhibitor PF-06869206 (6f) in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.
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