Design and Characterization of a Dual COX-2/Ca <sub>V</sub> 2.2 Inhibitor with Potent Analgesic Activity
Cyclooxygenase-2 (COX-2) and N-type voltage-gated calcium channels (Ca<sub>V</sub>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<sub>V</sub>2.2 inhibitors. Structure-activity relationship analysis identified compound <b>5d</b> as the lead candidate, exhibiting balanced inhibitory potency and favorable selectivity against COX-2 and Ca<sub>V</sub>2.2, with IC<sub>50</sub> values of 0.26 ± 0.17 μM and 0.29 ± 0.07 μM, respectively. In diverse models of inflammatory, neuropathic, and visceral pain, <b>5d</b> produced pronounced analgesic effects. By simultaneously suppressing inflammatory responses and disrupting the stepwise amplification of nociceptive signaling, <b>5d</b> embodies a multimechanistic analgesic strategy meriting further exploration.
Authors
- Shilong Hu
- Jie Qiu (ORCID: https://orcid.org/0000-0001-8186-9995)
- Dongxue Yang (ORCID: https://orcid.org/0000-0001-7128-9831)
- Bowen Ke
- Jianxing Liu (ORCID: https://orcid.org/0000-0002-2201-3887)
- Zhuang Miao
- Zhenbo Huang
- Wencheng Liu
- Tian Zhang
- Ao Hai
- Jianing Su
- Shouwei Tao
Institutions
- Academy of Medical Sciences (GB)
- Hainan University (CN)
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- Kulkarni reconstructive Urology Center (IN)
- Clinical Research Management (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-01-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02649
- Primary Topic
- Pain Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00