Drug discovery of CNS-penetrant histonedeacetylase inhibitors

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07008
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Kansai University
• Principal Investigator: Sumiyoshi Takaaki 関西大学, 化学生命工学部, 教授 (50738911)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: HDAC6阻害剤 / 構造活性相関 / 脳移行性 / 抗うつ薬

Outline of Final Research Achievements

Central nervous system (CNS) penetrant histone deacetylase (HDAC) inhibitors are the next-generation therapeutic agents based on a novel mechanism of action for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and psychiatric diseases such as depression. However, many HDAC inhibitors showed have low CNS penetration ability,and therefore we have no HDAC inhibitors approved for the treatment of neuropsychiatric disorders. To overcome the low CNS penetration of known HDAC inhibitors, we focused on the hybrid strategy of histamine H1 receptor antagonist and HDAC inhibitors. We designed, synthesized, and evaluated novel hybrid compounds including the moiety of histamine H1R receptor antagonists which showed high CNS penetration. As a result, we found highly potent,isozyme-selective and CNS-penetrant HDAC inhibitors.In particular, identified HDAC6 inhibitor KH-259 showed significant antidepressant activity in tail-suspension test in mice.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

うつ病などの精神疾患は現在の治療薬を用いて完全寛解させることは困難であり、新規作用機序を有する治療薬の開発が望まれている。活性発現に極性基が必須であるため脳移行性が確保できていない創薬標的は複数存在しており、極性基を保持しつつ脳移行性を向上させる手法が確立されれば新規精神疾患治療薬の効率的創出につながる。本研究では、脳移行性が高い抗ヒスタミン薬の構造とのハイブリッドにより、高い脳移行性と抗うつ活性を示すHDAC6阻害剤KH-259を見出した。KH-259は新規作用機序に基づく抗うつ薬になることが期待される。また本手法は脳移行性に課題がある創薬標的の創薬への応用が期待できる。