Citation: Dengqi Xue, Yani Liu, Yilin Zheng, Heling Niu, Liying Dong, Xiangshuo Ouyang, Siyu Song, Denggao Zhang, Qianwei Ge, Kewei Wang, Liming Shao. Design and synthesis of novel α-aminoamides derivatives as Nav1.7 inhibitors for antinociception[J]. Chinese Chemical Letters, ;2022, 33(3): 1643-1646. doi: 10.1016/j.cclet.2021.08.026 shu

Design and synthesis of novel α-aminoamides derivatives as Nav1.7 inhibitors for antinociception

Dengqi Xue ^{a, b, 1} ,
Yani Liu ^{c, 1,} ,
Yilin Zheng ^a ,
Heling Niu ^c ,
Liying Dong ^c ,
Xiangshuo Ouyang ^a ,
Siyu Song ^a ,
Denggao Zhang ^a ,
Qianwei Ge ^a ,
Kewei Wang ^c ,
Liming Shao ^{a, b, *,}

a.
School of Pharmacy, Fudan University, Shanghai 201203, China
b.
State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
c.
Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao 266071, China

liuyani@qdu.edu.cn

limingshao@fudan.edu.cn

Received Date: 4 July 2021
Revised Date: 19 July 2021
Accepted Date: 6 August 2021
Available Online: 12 August 2021

Figures(5)

Three novel series of α-aminoamides derivatives were designed and synthesized based on ralfinamide, and their Nav1.7 inhibitory activities were evaluated using manual patch clamp electrophysiology. Active compounds inhibited Nav1.7 with half maximal inhibitory concentration (IC₅₀) values ranging from 2.9 µmol/L to 21.4 µmol/L. Among them, the most potent compound 19h exhibited about 12-fold potency better than ralfinamide. The investigation of their structure-activity relationship gives a strategy to improve the Nav1.7 inhibition of ralfinamide analogues. Compound 19h was efficacious in antinociception in the mouse spared nerve injury (SNI) model of neuropathic pain without causing sedation in the open field test.
- α-Aminoamides,
- Sodium channel,
- Nav1.7 inhibitor,
- Chronic pain,
- Analgesia
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