Design and Characterization of a Dual COX-2/CaV2.2 Inhibitor with Potent Analgesic Activity.

Cyclooxygenase-2 (COX-2) and N-type voltage-gated calcium channels (CaV2.2) 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/CaV2.2 inhibitors. Structure-activity relationship analysis identified compound 5d as the lead candidate, exhibiting balanced inhibitory potency and favorable selectivity against COX-2 and CaV2.2, with IC50 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.