Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.

中文翻译：

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ONO-8430506：一种新型紫杉醇抑制剂，可增强紫杉醇在乳腺癌模型中的抗肿瘤作用。

溶血磷脂酸（LPA）是一种生物活性脂质介体，可引发许多生物学功能，包括平滑肌收缩，细胞运动，增殖和形态变化。LPA是自分泌素（ATX）由血浆中的细胞外溶血磷脂酰胆碱（LPC）内源性产生的。在本文中，我们报告了我们的药物化学努力，以确定一种新型且高效的ATX抑制剂ONO-8430506（20），具有良好的口服可用性。为了增强酶促ATX抑制活性，我们通过结构比较我们的命中化合物与内源性配体LPC设计了几种化合物。进一步优化以改善人体血浆中的药代动力学和增强ATX抑制活性导致鉴定出ONO-8430506（20），可增强紫杉醇在乳腺癌模型中的抗肿瘤作用。