Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1)

Abstract

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 () in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.

Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion

“…It is conceivable that PF-06869206 needs to be administered more frequently to maintain adequate plasma levels or that factors other than phosphate contribute to FGF23 production in CKD. Our studies confirmed those by Thomas et al (49), namely that an acute reduction in PTH levels occurs in wild-type mice upon treatment with a single dose of PF-06869206. However, there was no PTH-lowerring effect of the NPT2a inhibitor upon repeat dosing in 5/6 nephrectomized rats.…”

“…Acute administration of PF-06869206 at 300mg/kg to Npt2c -/mice ( Figures 3A-D In contrast to the findings in wild-type and Npt2c -/mice, administration of PF-06869206 in Npt2a -/mice failed to increase urinary phosphate excretion or to decrease plasma phosphate relative to vehicle or baseline levels at 2-4 hours or 24 hours after dosing (Figures 3E,F). These findings confirmed our in vitro data (49), namely that PF-06869206 selectively inhibits Npt2a and has no readily detectable phosphaturic activity in the absence of that transporter.…”

“…We previously reported the ability of PF-06869206 to reduce phosphate uptake in HEK293 cells stably expressing human, rat, or mouse NPT2a and in primary human proximal tubular cells, but not in cells expressing NPT2b or NPT2c (49). Here we further characterized the activity profile of PF-06869206 in vitro by measuring phosphate uptake in primary rat proximal renal tubule cells (PRTs) exposed to increasing concentrations of the inhibitor.…”

“…We recently described the discovery of orally bioavailable selective inhibitors of NPT2a that display concentration-dependent inhibition of phosphate uptake in human proximal tubular cells in vitro (49). We showed that the oral PK profile of one of these inhibitors, PF-06869206, is suitable for exploring the pharmacological effects of selective NPT2a inhibition in rodents.…”

Synthetic approaches and pharmaceutical applications of chloro-containing molecules for drug discovery: A critical review

“…The compound 376 was screened for their Sodium-Phosphate Cotransporter NaPi2a (SLC34A1) inhibitor activity and compound 376 (NaPi2a IC 50 ¼ 380 nM) was found to be good NaPi2a inhibitor. Compound 376 (PF-06869206) was the first orally bioavailable selective NaPi2a inhibitor and represented a pharmacological tool to probe the functional effects of selective NaPi2a inhibition in vivo [129].…”