Development of a water-soluble modifying group that is metabolically activated regardless of the chemical structure of the parent compound

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16421
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Chiba Institute of Science
• Principal Investigator: Takahashi Masato 千葉科学大学, 薬学部, 助教 (40738770)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: プロドラッグ / 加水分解酵素 / 生体機能利用 / 薬学 / 有機化学

Outline of Final Research Achievements

In this project, a water-soluble modifying group was designed considering the properties of hydrolases such as carboxylesterase in order to synthesize water-soluble prodrugs. Specifically, a modifying group that dissolves in aqueous solutions with a wide pH and is metabolically activated without being affected by the structure of the parent compound was investigated. By using phenytoin as a parent compound and introducing a dicarboxylate type modifying group, a prodrug that was dissolved in a neutral aqueous solution and easily metabolically activated in human liver microsomes was synthesized.

Free Research Field

薬物代謝学

Academic Significance and Societal Importance of the Research Achievements

薬にとって水溶性の低下は、経口剤の吸収率に影響を与えるだけでなく、注射剤としての使用にも大きな制限を与える。水溶性を向上させるために、最近では、多くの化合物に適応可能なプロドラッグ化法が盛んに研究されているが、水溶性が改善できたとしても、生体内での代謝活性化に失敗してしまうケースが多く存在する。本研究では、代謝活性化の問題を解決すべく、酵素の基質特異性を考慮して水溶性修飾基を合成した。この水溶性修飾基をフェニトインに導入することで、安定かつ中性溶液中で溶解するプロドラッグを開発した。