Storer R Ian, Pike Andy, Swain Nigel A, Alexandrou Aristos J, Bechle Bruce M, Blakemore David C, Brown Alan D, Castle Neil A, Corbett Matthew S, Flanagan Neil J, Fengas David, Johnson M Scott, Jones Lyn H, Marron Brian E, Payne C Elizabeth, Printzenhoff David, Rawson David J, Rose Colin R, Ryckmans Thomas, Sun Jianmin, Theile Jonathan W, Torella Rubben, Tseng Elaine, Warmus Joseph S
Worldwide Medicinal Chemistry, Pfizer Ltd, The Portway, Granta Park, Cambridge CB21 6GS, UK.
Pharmacokinetics, Dynamics and Metabolism, Pfizer Ltd, The Portway, Granta Park, Cambridge CB21 6GS, UK.
Bioorg Med Chem Lett. 2017 Nov 1;27(21):4805-4811. doi: 10.1016/j.bmcl.2017.09.056. Epub 2017 Sep 28.
The discovery and selection of a highly potent and selective Na1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.
本文公开了一种专门为静脉输注设计的高效且选择性的Na1.7抑制剂PF-06456384的发现与筛选。文中讨论了广泛的体外药理学和ADME分析，以及随后的体内临床前PK和疗效模型数据。还提供了该化合物的一种推测的蛋白质-配体结合模式，以解释其在抑制相关钠通道方面的高效力和高选择性。为进一步支持所提出的结合模式，描述了强效缀合物，这些缀合物展示了开发化学探针以进行进一步靶点评估的潜力。
