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

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

Journal of medicinal chemistry (2016-01-07)
Kim Huard, James R Gosset, Justin I Montgomery, Adam Gilbert, Matthew M Hayward, Thomas V Magee, Shawn Cabral, Daniel P Uccello, Kevin Bahnck, Janice Brown, Julie Purkal, Matthew Gorgoglione, Adhiraj Lanba, Kentaro Futatsugi, Michael Herr, Nathan E Genung, Gary Aspnes, Jana Polivkova, Carmen N Garcia-Irizarry, Qifang Li, Daniel Canterbury, Mark Niosi, Nicholas B Vera, Zhenhong Li, Bhagyashree Khunte, Jaclyn Siderewicz, Timothy Rolph, Derek M Erion
PMID26734723
ABSTRACT

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.