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.

ABSTRACT

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 IC50 = 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.