The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a propeller-shape topology ensured the desired PI3Kδ selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound 18. This novel inhaled selective PI3Kδ inhibitor displayed durable anti-inflammatory activity in a disease-relevant rat model of Th-2-driven acute lung inflammation and safe in vitro and in vivo preclinical profiles. Therefore, compound 18 showed the appropriate discovery profile and was progressed to clinical trials in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients as CHF-6523.

中文翻译：

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CHF-6523 的发现，CHF-6523 是一种吸入选择性 PI3Kδ 抑制剂，用于治疗慢性阻塞性肺疾病


继续设计吸入选择性磷脂酰肌醇 3-激酶 δ （PI3Kδ） 抑制剂治疗炎症性肺病。能够采用螺旋桨形拓扑结构的新型异香豆素支架的基于知识的设计确保了所需的 PI3Kδ 选择性。通过铰链结合剂基团优化实现低纳摩尔细胞效力，通过头基优化降低内在通透性以延长肺滞留，以及筛选适合作为干粉给药的结晶形式，最终鉴定出化合物 18。这种新型吸入选择性 PI3Kδ 抑制剂在 Th-2 驱动的急性肺部炎症的疾病相关大鼠模型中显示出持久的抗炎活性，并且在体外和体内临床前特征中是安全的。因此，化合物 18 显示出适当的发现特征，并以 CHF-6523 的形式在健康志愿者和慢性阻塞性肺病 （COPD） 患者中进行临床试验。