The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (8) was discovered from a highly selective high-throughput screening hit via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed.

中文翻译：

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（S）-6-（1-（6-（1-甲基-1 H-吡唑-4-基）-[1,2,4]三唑并[4,3 - b ]哒嗪-3-基）的教训乙基）喹啉（PF-04254644），一种受体酪氨酸激酶c-Met的抑制剂，具有高蛋白激酶选择性，但广泛的磷酸二酯酶家族抑制导致大鼠心肌变性

肝细胞生长因子（HGF）/ c-Met信号转导轴在许多癌症中均失控，并且在肿瘤侵袭性生长和转移中起重要作用。完全选择性的c-Met抑制剂（S）-6-（1-（6-（1-甲基-1 H-吡唑-4-基）-[1,2,4]三唑并[4,3- b ]吡嗪通过基于结构的药物设计和药物化学线索优化，从高选择性高通量筛选中发现了-3-基）乙基）喹啉（8）。化合物8具有许多吸引人的特性，值得临床前评估。确定了广泛的脱靶屏幕8作为泛磷酸二酯酶（PDE）家族抑制剂，在大鼠体内安全性评估中与心率持续增加，心输出量增加和收缩指数降低以及心肌退化有关。由于心脏相关安全性的治疗窗口狭窄，化合物8被终止为临床前候选药物。讨论了从多参数先导优化中学习的知识以及在药物发现后期避免毒性消耗的策略。