A series of inhibitors of Autotaxin (ATX) has been developed using the binding mode of known inhibitor, PF-8380, as a template. Replacement of the benzoxazolone with a triazole zinc-binding motif reduced crystallinity and improved solubility relative to PF-8380. Modification of the linker region removed hERG activity and led to compound 12 – a selective, high affinity, orally-bioavailable inhibitor of ATX. Compound 12 concentration-dependently inhibits autotaxin and formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic experiments.

中文翻译：

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紫杉醇抑制剂的开发：一系列结合锌的三唑

使用已知抑制剂PF-8380的结合模式作为模板，已经开发了一系列自分泌运动抑制剂（ATX）。相对于PF-8380，用三唑锌结合基序取代苯并恶唑酮可降低结晶度并提高溶解度。接头区域的修饰去除了hERG活性，并产生了化合物12 –一种选择性，高亲和力，口服生物利用度的ATX抑制剂。如药代动力学-药效学实验中所示，化合物12在体内浓度依赖性地抑制自分泌紫杉醇和LPA的形成。