2. Academic Validation
  3. 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

  • 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

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.
PMID: 26734723 DOI: 10.1021/acs.jmedchem.5b01752
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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