A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progressed to an acute toxicity study in a rodent model. Strikingly, acute toxicity was observed in mice. Experiments measuring cellular respiration showed a dose-dependent inhibition of mitochondrial respiration. Under these conditions, potent cytotoxicity was observed for these compounds in rat hepatocytes suggesting that the potent acute mammalian toxicity of this chemotype is most likely associated with respiratory inhibition. In contrast, parasite toxicity was not correlated to acute toxicity or cytotoxicity in respiring cells. This paper highlights the importance of identifying an appropriate in vitro predictor of in vivo toxicity early on in the drug discovery pipeline, in particular assessment for in vitro mitochondrial toxicity.

中文翻译：

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1-甲基-1 H-吡唑-5-羧酰胺衍生物表现出意外的急性哺乳动物毒性

合成了一系列1-甲基-1 H-吡唑-5-羧酰胺作为强效抑制绵羊线虫Haemonchus contortus线虫的抑制剂。。这些化合物在标准体外培养条件下对一系列哺乳动物细胞系没有明显的细胞毒性，具有高选择性指数，并已在啮齿动物模型中进行了急性毒性研究。惊人地，在小鼠中观察到急性毒性。测量细胞呼吸的实验表明，剂量依赖性抑制线粒体呼吸。在这些条件下，在大鼠肝细胞中观察到了这些化合物的强力细胞毒性，这表明这种化学型的强力急性哺乳动物毒性很可能与呼吸抑制有关。相反，寄生虫毒性与呼吸细胞的急性毒性或细胞毒性无关。本文着重指出了在药物开发流程中及早发现合适的体内毒性体外预测因子的重要性，