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

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

  • J Med Chem. 2026 Feb 12;69(3):2725-2745. doi: 10.1021/acs.jmedchem.5c02649.
Jie Qiu 1,  Shouwei Tao 1,  Tian Zhang 1,  Zhuang Miao 1,  Shilong Hu 1,  Wencheng Liu 1,  Jianing Su 2,  Ao Hai 1,  Zhenbo Huang 3,  Jin Liu 1 4,  Dongxue Yang 5,  Bowen Ke 1 3
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2 West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 4 Clinical Research Center, Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen 518107, China.
  • 5 Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan 610044, China.
PMID: 41612170 DOI: 10.1021/acs.jmedchem.5c02649
Abstract

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.

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