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BAY-9835:发现了第一个口服生物可用的ADAMTS7抑制剂

Daniel Meibom¹, Pierre Wasnaire¹, Kristin Beyer¹

¹Bayer AG, 42113 Wuppertal, Germany.

Journal of medicinal chemistry

|February 13, 2024

概括

研究人员开发了BAY-9835,这是第一个口服生物可用抑制剂,向ADAMTS7 (冠状动脉疾病中的关键酶). 这一发现为心血管疾病提供了新的治疗途径.

科学领域:

生物化学和药物化学医学化学
心血管疾病研究研究
药物发现和开发药物发现和开发

背景情况:

通过全基因组关联研究,ADAMTS7是一种矩阵金属蛋白酶,与冠状动脉疾病 (CAD) 的发展有关.
该酶的蛋白质分解活性在血管损伤后的动脉生成和复原中至关重要.

研究的目的:

设计和优化针对ADAMTS7.7的催化域的新型抑制剂.
开发一种口服生物可利用的ADAMTS7抑制剂,用于潜在的心血管疾病治疗应用.

主要方法:

在基于现有的ADAMTS4/ADAMTS5抑制剂的ADAMTS7抑制剂的设计.
使用X射线晶体学进行结构引导优化,以增强对MMP的选择性12.
化学修饰,包括添加5个成员的异味组,以提高功效.
药理动力学 (DMPK) 特性微调以实现口服生物可用性.

主要成果:

最初的抑制剂对MMP12的选择性有限.
利用ADAMTS7和MMP12之间的结合位点差异显著提高了选择性.
优化导致强大的ADAMTS7抑制和有利的DMPK特性.
BAY-9835被确定为第一个口服生物可用ADAMTS7抑制剂.

结论:

BAY-9835代表了作为第一个口服生物可用的ADAMTS7抑制剂的重大进展.
这项研究表明,基于结构的药物设计策略是针对ADAMTS7.7的成功策略.
对ADAMTS12的选择性进行进一步优化是可行的,这表明持续的治疗潜力.

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