发现新的11个成员模板作为烯合成酶抑制剂
Noriyasu Haginoya1, Masanori Suzuki2, Makoto Suzuki1
1Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, 134-8630 Tokyo, Japan.
Journal of medicinal chemistry
|March 22, 2024
概括
新的11个成员环化合物有效抑制素合成酶,导致胆固醇水平降低. 异构体A-(1S,3R) -14i在动物研究中表现出显著的血脂降低作用,促进了超脂血症治疗.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 生物化学 生物化学
背景情况:
- 烯合成酶是通过降低肝脏胆固醇来治疗高脂血症的关键标.
- 以前的基类抑制剂显示出强烈的活性,但缺乏足够的体内疗效.
- 提高口服合成酶抑制剂的生物可用性和体内疗效对于治疗开发至关重要.
研究的目的:
- 设计和合成新型循环11个成员环素合成酶抑制剂.
- 为了增强现有的抑制剂支架的降胆固醇潜力和口服活性.
- 评估新开发的烯合成酶抑制剂的体内疗效.
主要方法:
- 医药化学的努力集中在创造循环的11个成员的环状结构上.
- 基于改进模板的新型化合物系列的合成.
- 在体外测试中评估烯合成酶抑制活性.
- 在 hamster 和 marmoset 模型中对血脂降低效应的体内评估.
主要成果:
- 开发了一系列新型的循环化11个成员环化合物,具有强大的素合成酶抑制活性.
- 化合物异构体A-(1S,3R) -14i在重复剂量研究中显示出显著的血脂降低功效.
- 新的化学实体显示出作为治疗高脂血症的口服活性剂的前景.
结论:
- 这项研究成功地确定了11个成员环素合成酶抑制剂,其 in vivo 疗效得到改善.
- 异构体A-(1S,3R) -14i代表了作为抗高脂血症药物进一步开发的有希望的候选者.
- 这些发现为设计下一代烯合成酶抑制剂提供了宝贵的见解.
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