Design,synthesis And Biological Evaluation Of Novel Triazole EP4 Antagonist For The Treatment Of Osteoarthritis

Osteoarthritis is a disease that is mainly composed of various cytokines and inflammatory mediators,and is mainly damaged by articular cartilage.Currently,most of the drugs represented by NSAIDs can only relieve pain and can’t repair the cartilage,so it can’t cure osteoarthritis completely.As a proinflammatory factor,PGE₂ can induce osteoarthritis by inducing MMP-13 enzyme to degrade cartilage matrix.The EP4receptor is involved in the regulation of osteoarthritis induced by PGE₂ and plays a very important role in the occurrence and development of osteoarthritis.Therefore,the EP4receptor is an important target for the treatment of osteoarthritis.EP4 receptor antagonist provides new ideas for the treatment of osteoarthritis.After many years of research,many selective and potent EP4 antagonists have entered clinical trials.The first generation EP4 antagonists are amide sulfonamide compounds,most of which have defects in poor physical and chemical properties.The second generation EP4 antagonists with the structure of amido methyl benzoic acid have good stability.Based on the second generation EP4 antagonist amido methyl benzoic acid as the basic skeleton structure,we designed and synthesized two kinds of1,2,3-triazole compounds of 1,4 and 1,5.After the early configuration identification and activity screening,the B7 of the 1,5 structure was determined.Through biological activity screening,all of the compounds had good EP4 antagonistic activity.The EP4antagonistic activity of compounds B26 and B27 reached 3 nM,compared with the positive compound E7046,the activity increased by ten times.The toxicity and selectivity of the compounds and the effect on the expression of MMP-13 were systematically evaluated.We selected B26,an excellent compound,for osteoarthritis in vivo,and found that the compound exhibited good cartilage repair ability.As a potent EP4 receptor antagonist,this kind of compound has potential for further development,and is expected to provide more options for the study of osteoarthritis.