二羧酸系列用于溶质载体13（SLC13）家族体内抑制柠檬酸转运的优化
Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family.
作者信息
Huard Kim, Gosset James R, Montgomery Justin I, Gilbert Adam, Hayward Matthew M, Magee Thomas V, Cabral Shawn, Uccello Daniel P, Bahnck Kevin, Brown Janice, Purkal Julie, Gorgoglione Matthew, Lanba Adhiraj, Futatsugi Kentaro, Herr Michael, Genung Nathan E, Aspnes Gary, Polivkova Jana, Garcia-Irizarry Carmen N, Li Qifang, Canterbury Daniel, Niosi Mark, Vera Nicholas B, Li Zhenhong, Khunte Bhagyashree, Siderewicz Jaclyn, Rolph Timothy, Erion Derek M
机构信息
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.
出版信息
J Med Chem. 2016 Feb 11;59(3):1165-75. doi: 10.1021/acs.jmedchem.5b01752. Epub 2016 Jan 27.
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.
抑制钠偶联柠檬酸转运体（NaCT或SLC13A5）已被提议作为预防和治疗代谢性疾病的一种新的治疗方法。在之前的一份报告中，我们发现了二羧酸酯1a（PF-06649298），它通过与NaCT的特异性相互作用在体外和体内环境中抑制柠檬酸的转运。在此，我们报告了该系列化合物的优化，得到了4a（PF-06761281），这是一种更有效的抑制剂，具有适合评估体内药效学的体内药代动力学特征。化合物4a用于证明在体内对肝脏和肾脏中放射性[¹⁴C]柠檬酸摄取的剂量依赖性抑制，导致血浆葡萄糖浓度适度降低。
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