Design and synthesis of Prostanoid EP4 receptor antagonists for treatment of inflammatory pain

Prostaglandin E2 (PGE2) is the principal proinflammatory prostanoid and is implicated in the pathogenesis of a number of diseases such as pain, fever, arthritis and cancer. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust anti-inflammation and analgesic effect represents an attractive therapy strategy. A series of urea-containing derivatives of novel benzopyrazole scaffold were designed and synthesized through a scaffold hopping strategy. The most promising compound 27i exhibited the best inhibitory activity against EP4 (27i hEP4 IC₅₀ = 6.40 nM). In a mouse model of arthritis (AIA) induced by Freund's complete adjuvant (CFA), compound 27i significantly reduced the swelling of paws and joints, inflammatory cell infiltration, cartilage damage, pannus formation and bone erosion in the joints of AIA mice in a dose-dependent manner. In the ear swelling model, the anti-inflammatory effect of compound 27i was superior to celecoxib and E7046. Besides, 27i possessed good in vivo tolerability in subacute safety evaluation. Collectively, this study provided valuable lead compounds for the treatment of inflammation and pain, which were worthy of further development.