α-Cl-α-Br-phosphonoacetic acid is a potent and selective inhibitor of Na +/Pi cotransport across renal cortical brush border membrane

We found that α-Cl-α-Br-phosphonoacetate (ClBrPAA) is a competitive, solute-specific inhibitor of Na +/Pi cotransport across renal cortical brush border membrane. Inhibition by ClBrPAA (Ki = 62 μM) is more than three times more effective than inhibition by phosphonoformate (PFA), the most potent Na +/Pi cotransport inhibitor known to date, and 26 times more effective than the parent compound, phosphonoacetate (PAA). These observations indicate that substitution of bromine and chlorine atoms at the α-carbon of PAA greatly enhances its efficacy as a competitive inhibitor of Na +/Pi cotransport. As ClBrPAA is much less inhibitory than PAA and PFA towards viral DNA polymerases and did not inhibit human α-DNA polymerase (ref. 10), the results also demonstrate that Na +/Pi cotransport inhibition can be dissociated from inhibition of DNA polymerases by phosphonocarboxylate compounds.