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托邦化合物的α-化及其对物理化学和ADME特性的影响

Tamaki Hoshikawa¹, Toshiki Kurokawa¹, Hikaru Yoshimura¹

¹Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.

Bioorganic & medicinal chemistry letters

|May 16, 2024

概括

通过电化学合成化多化合物,提高了药物相似性,增强了膜透性,减少了通道负担. 然而,水溶性和稳定性下降,基本性显著降低.

科学领域:

有机化学有机化学
药用化学医学化学
电化学电化学电化学

背景情况:

热邦类化合物是具有多种药理活动的重要自然产品类别.
修改托邦支架对于开发具有改进性质的新疗法至关重要.
化是药物化学中常见的一种策略,用于调节药理动力学和药理动力学特征.

研究的目的:

通过电化学C(sp3) -H化反应合成新型的α-化特罗类型.
评估阿尔法化对托邦化合物的药物相似性参数的影响.
为了比较化特罗潘与其非化母化合物的特性.

主要方法:

电化学合成的α-化特罗潘化合物.
药物相似性参数的评估,包括膜透性,P-gp负担和通道抑制 (hERG,Na(v) 1.5).
测量原子的水溶性,微体稳定性和基本性.

主要成果:

成功合成了一系列的α-化多化合物.
观察到膜透性的改善和减少P-gp的责任.
证明了对hERG和Na(v) 1.5通道的抑制作用降低.
发现水溶性和微体稳定性下降的趋势.
量化了显著的减少 (约. 1000倍) 在由于α-化而产生的托帕原子的基本性.

结论:

电化学C(sp3)-H化是一种有效的合成α-化特罗潘的方法.
阿尔法化对关键的药物相似性参数产生积极影响,包括透性和通道相互作用.
观察到的溶解度和稳定性的权衡需要在药物设计中考虑.
降低托帕的基本性是α-化的一个关键后果,对受体结合和药理动力学有潜在的影响.

关键词:

在C-H功能化方面.电化学电化学电化学化化化化

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