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

Journal of medicinal chemistry

PubMedID: 26734723

Huard K, Gosset JR, Montgomery JI, Gilbert AM, Hayward MM, Magee TV, Cabral S, Uccello DP, Bahnck KB, Brown JA, Purkal J, Gorgoglione MF, Lanba A, Futatsugi K, Herr M, Genung N, Aspnes GE, Polivkova J, Garcia-Irizarry CN, Li Q, Canterbury DP, Niosi M, Vera NB, Li Z, Khunte B, Siderewicz J, Rolph TP, Erion DM. Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family. J Med Chem. 2016;.
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 [(14)C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations.