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 (6f) in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.

Figure 1

Representative nonselective literature NaPi2 inhibitors.

Scheme 1. Synthesis of Azaindole Analogues

Reagents and conditions: (a) amine, i-Pr₂NEt, CH₃CN, 80 °C or amine, i-Pr₂NEt, CsF, CH₃CN, 120 °C; (b) NCS, DMF, 20–30 °C.

Scheme 2. Synthesis of Azaindole Analogue 6f

Reagents and conditions: (a) i-Pr₂NEt, CH₃CN, −10 to −5 °C, 87%; (b) DBU, CH₃CN, 90 °C, 70%; (c) POCl₃, CH₃CN, 60 °C, 90%; (d) NCS, DMF, 30 °C, 76%; (e) i-Pr₂NEt, CH₃CN, 80 °C, 86%.

Figure 2

Inhibition of phosphate uptake in human proximal tubule cells by (A) 1, (B) 6b, and (C) 6e compared with PFA. All three experiments from one donor. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001; one-way ANOVA with Dunnett’s comparison to 0 μM control.