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发现和优化Pyridazinones作为PI3Kδ选择性抑制剂通过吸入进行管理
Paolo Bruno1, Alessandra Micoli2, Mauro Corsi3
1Medicinal Chemistry and Drug Design Technologies Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
Journal of medicinal chemistry
|June 22, 2024
概括
研究人员开发了针对炎症性呼吸道疾病的新型吸入型小分子抑制剂,向酸丁醇3-激酶 (PI3K). 化合物26在内给药后显示出有希望的体内药理动力学,验证了体内转化为体内转化.
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.
- 呼吸系统医学 呼吸系统医学
背景情况:
- 炎症性呼吸道疾病代表着一个重要的未满足的医疗需求.
- 酸氨基3-激酶 (PI3K) 信号通路与炎症有关.
- 吸入疗法的开发为呼吸系统疾病提供了有针对性的治疗.
研究的目的:
- 确定PI3K的新型小分子抑制剂,用于治疗炎症性呼吸道疾病.
- 优化用于吸入输送的化合物,重点关注药理和ADME特性.
- 评估化合物的体内疗效和药理动力学特征.
主要方法:
- 一个pyridazin-3(2H) 一脚手架的设计和合成,具有三个多样化点.
- 探索化学多样性以优化PI3Kδ选择性,细胞效能和ADME特性.
- 在体内模型中进行化合物26的内注射.
主要成果:
- 实现了PI3Kδ选择性和细胞功能的期望调节.
- 优化吸收,分布,新陈代谢和分泌 (ADME) 特性,适合吸入.
- 化合物26在内给药时显示出有前途的药物动力学特征.
结论:
- 开发的pyridazin-3(2H) -one支架是一个多功能平台,用于发现吸入PI3K抑制剂.
- 优化策略成功地将体外资料转化为体外表现.
- 这种方法有可能开发用于炎症性呼吸道疾病的新吸入疗法.
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