Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid. Compound 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients.

中文翻译：

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2-[[2-乙基-6- [4- [2-（3-羟基氮杂环丁烷-1-基）-2-氧代乙基]哌嗪-1-基] -8-甲基咪唑并[1,2- a ]吡啶的发现-3-yl] methylamino] -4-（4-氟苯基）噻唑-5-腈（GLPG1690），一种用于治疗特发性肺纤维化的一流的自分泌运动抑制剂，正在接受临床评估

Autotaxin是一种循环酶，在血液中产生溶血磷酸（LPA）物种中起主要作用。在许多疾病领域，包括肺纤维化中，已经提出了autotaxin / LPA轴的作用。已知自分泌运动抑制素抑制剂前导化合物1的结构修饰，以减轻hERG抑制作用，消除CYP3A4时间依赖性抑制作用并改善药代动力学特性，从而导致了临床候选药物GLPG1690的鉴定（11）。化合物11能够在体内血浆中持续降低LPA水平，并且在博莱霉素诱导的小鼠肺纤维化模型中有效，并在减少肺部细胞外基质沉积的同时，还降低了支气管肺泡灌洗液中LPA 18：2的含量体液。目前正在针对特发性肺纤维化患者的2a探索期研究中对化合物11进行评估。