In the kidney proximal tubule, glomerular-filtered phosphate is in part reabsorbed by the sodium-phosphate co-transporter 2a, or NaPi2a.  This is a solute carrier (SLC) transporter encoded by the SLC34A1 gene.  A NaPi2a inhibitor is hypothesized to facilitate urinary phosphate excretion and envisioned as a therapy to correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease – mineral and bone disorder (CKD-MBD).  A high-throughput screen was run using SLC34A1-transfected cells whereby the uptake of <sup>33</sup>P-radiolabeled phosphate was detected.  A hit from this effort was then optimized to PF-06869206, a useful NaPi2a-selective tool compound with good oral bioavailability.  PF-06869206 and its series show excellent selectivity for NaPi2a over the other sodium-phosphate co-transporters, the first known chemical matter to show such selectivity.  This compound was used to explore the in vitro and in vivo pharmacology of selective NaPi2a inhibition including an 8-week study in a rodent model of cardio-renal disease.<br/>

Discovery of a series of selective inhibitors of the sodium-phosphate co-transporter NaPi2a (SLC34A1)

256th National Meeting (2018)

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