Design, synthesis, and biological evaluation of arylmethylpiperidines as Kv1.5 potassium channel inhibitors

Abstract

Kv1.5 potassium channel, encoded by KCNA5, is a promising target for the treatment of atrial fibrillation, one of the common arrhythmia. A new series of arylmethylpiperidines derivatives based on DDO-02001 were synthesised and evaluated for their ability to inhibit Kv1.5 channel. Among them, compound DDO-02005 showed good inhibitory activity (IC₅₀ = 0.72 μM), preferable anti-arrhythmic effects and favoured safety. These results indicate that DDO-02005 can be a promising Kv1.5 inhibitor for further studies.

Graphical abstract

Key Words:

• Kv1.5 inhibitors
• atrial fibrillation
• anti-arrhythmia

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

We are thankful for the financial support of the National Natural Science Foundation of China [grant number 81872799], [grant number 81930100], [grant number 81773639]; the Natural Science Foundation of Jiangsu Province of China [grant number BK 20191321]; Fundamental Research Funds for the Central Universities [grant number 2632018ZD14]; the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” of China [grant number 2018ZX09711002]; the Double First Class Innovation Team of China Pharmaceutical University [grant number CPU2018GY02]; the Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education; the Open Project of State Key Laboratory of Natural Medicines [grant number SKLNMZZCX201803]; the Priority Academic Program Development of Jiangsu Higher Education Institutions; and the Natural Science Research Project of Jiangsu Higher Education [grant number 20KJB350001].