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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：1165-1175
• 全文大小：507K
• ISSN：1520-4804

文摘

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.