Identification and evaluation of cyclic urea based 4H-triazolo pyridine substituted derivatives as novel ASK1 inhibitors

Apoptosis signal-regulating kinase 1 (ASK1) is a member of MAPK signaling pathway and implicated in numerous human diseases including hepatic injury. In the current study we have designed and synthesized 4H-triazolo pyridine substituted derivatives as novel ASK1 inhibitors. Evaluation of multiple synthesized compounds in in-vitro cell-free assay for best compounds (29, IC₅₀ = 4.1 nM; 33, IC₅₀ = 3.6 nM; 35, IC₅₀ = 1.8 nM) and cell based assay (29, IC₅₀ = 139.5 nM; 33, IC₅₀ = 69.2 nM; 35, IC₅₀ = 15.1 nM) led us to identify potent ASK1 inhibitors 29, 33 and 35. Therapeutic potential of these selected compounds (29, 33 and 35) was tested in preclinical mouse model of acetaminophen (APAP)-induced hepatic injury. All compounds exhibited significant protection against hepatotoxicity as evident from reduction in plasma ALT levels. Further, all these compounds displayed a notable metabolic stability in mouse hepatocytes and exhibited excellent safety profile as no significant CYP450 or hERG channel inhibition was found. Overall, these results indicated that our compounds are potent ASK1 inhibitors and have therapeutic potential to protect the liver against critical damage.

4H-triazolo pyridine; ALT; ASK1; Hepatotoxicity.