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1-Methyl-1H-pyrazole-5-carboxamide Derivatives Exhibit Unexpected Acute Mammalian Toxicity.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Preston S,Garcia-Bustos J,Hall LG,Martin SD,Le TG,Kundu A,Ghoshal A,Nguyen NH,Jiao Y,Ruan B,Xue L,Huang F,Chang BCH,McGee SL,Wells TNC,Palmer MJ,Jabbar A,Gasser RB,Baell JB

doi

10.1021/acs.jmedchem.0c01793

subject

Has Abstract

pub_date

2021-01-14 00:00:00

pages

840-844

issue

1

eissn

0022-2623

issn

1520-4804

journal_volume

64

pub_type

杂志文章

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