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

  • J Med Chem. 2016 Feb 11;59(3):1165-75. doi: 10.1021/acs.jmedchem.5b01752.
Kim Huard  1  2 James R Gosset  1  2 Justin I Montgomery  1  2 Adam Gilbert  1  2 Matthew M Hayward  1  2 Thomas V Magee  1  2 Shawn Cabral  1  2 Daniel P Uccello  1  2 Kevin Bahnck  1  2 Janice Brown  1  2 Julie Purkal  1  2 Matthew Gorgoglione  1  2 Adhiraj Lanba  1  2 Kentaro Futatsugi  1  2 Michael Herr  1  2 Nathan E Genung  1  2 Gary Aspnes  1  2 Jana Polivkova  1  2 Carmen N Garcia-Irizarry  1  2 Qifang Li  1  2 Daniel Canterbury  1  2 Mark Niosi  1  2 Nicholas B Vera  1  2 Zhenhong Li  1  2 Bhagyashree Khunte  1  2 Jaclyn Siderewicz  1  2 Timothy Rolph  1  2 Derek M Erion  1  2
Affiliations
  • 1. Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.
  • 2. Worldwide Medicinal Chemistry, and ⊥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
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.

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