Design and Characterization of a Dual COX-2/Ca V 2.2 Inhibitor with Potent Analgesic Activity

Cyclooxygenase-2 (COX-2) and N-type voltage-gated calcium channels (Ca V 2.2) play pivotal roles in mediating inflammatory responses and regulating neuronal excitability in chronic pain. Concurrent modulation of these targets can achieve synergistic analgesic effects. We designed and synthesized a series of diarylpyrazole-based dual COX-2/Ca V 2.2 inhibitors. Structure–activity relationship analysis identified compound 5d as the lead candidate, exhibiting balanced inhibitory potency and favorable selectivity against COX-2 and Ca V 2.2, with IC 50 values of 0.26 ± 0.17 μM and 0.29 ± 0.07 μM, respectively. In diverse models of inflammatory, neuropathic, and visceral pain, 5d produced pronounced analgesic effects. By simultaneously suppressing inflammatory responses and disrupting the stepwise amplification of nociceptive signaling, 5d embodies a multimechanistic analgesic strategy meriting further exploration.