Discovery of 4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide derivatives as novel anti-inflammatory agents for the treatment of acute lung injury and sepsis

Yang, Jun; Yang, Xu; Li, Xiang; Zhou, Ying; Dai, Jintian; Li, Xiaobo; Chen, Pan; Chen, Gaozhi; Cho, Won‐Jea; Chattipakorn, Nipon; Самородов, Александр В.; Павлов, В. Н.; Wang, Yi; Liang, Guang; Tang, Qidong

doi:10.1016/j.ejmech.2023.115144

Cited by 7 publications

(1 citation statement)

References 44 publications

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“…As depicted in Scheme 3, 9a−9d was formed by reacting nitrophenol derivatives with 5a and 5b at a high temperature (140 °C), then reduced by Fe to obtain 10a−10d. 36 Finally, J9−J30 was obtained by condensation reaction.…”

Section: Introductionmentioning

confidence: 99%

Discovery of the Diphenyl 6-Oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide Analogue J27 for the Treatment of Acute Lung Injury and Sepsis by Targeting JNK2 and Inhibiting the JNK2-NF-κB/MAPK Pathway

Liao,

Yang,

et al. 2023

J. Med. Chem.

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Acute lung injury (ALI) and sepsis are both serious and complex conditions associated with high mortality, yet there are no effective treatments. Herein, we designed and synthesized a series of diphenyl 6-oxo-1,6-dihydropyridazine-3-carboxylate/ carboxamide analogues exhibiting anti-inflammatory activity. The optimal compound J27 decreased the release of TNF-α and IL-6 in mouse and human cells J774A.1 and THP-1 (IL-6 IC 50 = 0.22 μM) through the NF-κB/MAPK pathway. J27 demonstrated remarkable protection against ALI and sepsis in vivo and exhibited good safety in subacute toxicity experiments. Pharmacokinetic study indicated that J27 had good bioavailability (30.74%). To our surprise, J27 could target JNK2 with a totally new molecular skeleton compared with the only few JNK2 inhibitors reported. Moreover, there is no report that JNK2 inhibitors could apply for ALI and sepsis. Therefore, this work provides a new lead structure for the study of JNK2 inhibitors and a new target of JNK2 to treat ALI and sepsis.

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Section: Introductionmentioning

confidence: 99%