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

Autor:	Huard K; 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., Gosset JR; 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., Montgomery JI; 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., Gilbert A; 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., Hayward MM; 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., Magee TV; 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., Cabral S; 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., Uccello DP; 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., Bahnck K; 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., Brown J; 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., Purkal J; 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., Gorgoglione M; 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., Lanba A; 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., Futatsugi K; 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., Herr M; 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., Genung NE; 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., Aspnes G; 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., Polivkova J; 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., Garcia-Irizarry CN; 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., Li Q; 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., Canterbury D; 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., Niosi M; 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., Vera NB; 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., Li Z; 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., Khunte B; 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., Siderewicz J; 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., Rolph T; 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., Erion DM; 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.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2016 Feb 11; Vol. 59 (3), pp. 1165-75. Date of Electronic Publication: 2016 Jan 27.
DOI:	10.1021/acs.jmedchem.5b01752
Abstrakt:	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.
Databáze:	MEDLINE
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