Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

Inhibition of the sodium-coupled
citrate transporter (NaCT or SLC13A5)
has been proposed as a new therapeutic approach for prevention and
treatment of metabolic diseases. In a previous report, we discovered
dicarboxylate 1a (PF-06649298) which inhibits the transport
of citrate in in vitro and in vivo
settings via a specific interaction with NaCT. Herein, we report the
optimization of this series leading to 4a (PF-06761281),
a more potent inhibitor with suitable in vivo pharmacokinetic profile
for assessment of in vivo pharmacodynamics. Compound 4a was used to demonstrate dose-dependent inhibition of radioactive
[14C]­citrate uptake in liver and kidney in vivo, resulting
in modest reductions in plasma glucose concentrations.