Effects of deuterium modification on the electropharmacological profile of anti-atrial fibrillatory drug

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16136
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Toho University
• Principal Investigator: Kambayashi Ryuichi 東邦大学, 医学部, 助教 (70837492)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 重水素化 / 抗不整脈薬 / 心房細動 / 病態モデル / QT延長 / 心室不整脈

Outline of Final Research Achievements

To investigate how deuteration can modify electropharmacological effects of antiarrhythmic drug, we assessed the effects of deuterated analogue of dronedarone, poyendarone, using the canine atrial fibrillation models, which were compared with those of dronedarone. The deuteration might enhance the drug-induced prolongation of atrial effective refractory period at high frequency of depolarization observed during AF episode, which can potentiate the inhibitory action on the paroxysmal atrial fibrillation. Meanwhile, the deuteration would hardly affect the defibrillation effect on the persistent atrial fibrillation, whereas it can attenuate the risk for QT prolongation and ventricular arrhythmias. Poyendarone would have more potent anti-atrial fibrillatory action and favorable cardiovascular safety profile than dronedarone, and therefore is a promising anti-atrial fibrillatory drug candidate.

Free Research Field

循環薬理学

Academic Significance and Societal Importance of the Research Achievements

心房細動の治療に使用される既存の抗不整脈薬は、心房組織への選択性または心房細動の病態に対する特異性が低く、心室組織に対しても電気生理学的作用を示し、致死性心室不整脈を誘発する可能性がある。本研究は、その有害作用を減弱する手段として重水素化に着目し、重水素化は抗不整脈薬の心房細動に対する有効性を増強し、心室不整脈の誘発リスクを減弱することを示した。それゆえ、重水素化が抗不整脈薬の循環薬理作用を修飾する上で有益な手段となる可能性を見出した。既存薬dronedaroneの重水素化誘導体poyendaroneは、より有効かつ安全な治療薬として心房細動患者の薬物治療に貢献できると考える。