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

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Worldwide Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
Worldwide Medicinal Chemistry, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
*K.H.: phone, 1-617-522-3302; e-mail, [email protected]
*D.M.E.: phone, 1-617-551-3755; e-mail, [email protected]
Cite this: J. Med. Chem. 2016, 59, 3, 1165–1175
Publication Date (Web):January 6, 2016
Copyright © 2016 American Chemical Society

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    Abstract Image

    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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b01752.

    • Synthesis and characterization of all intermediates, in vitro selectivity data for 4a, X-ray crystal structure of 7a, fa assessment, exposure of compounds 1a and 4a for in vivo experiments (PDF)

    • Molecular formula strings (CSV)

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