Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122, Parma, Italy.
Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy.
Eur J Med Chem. 2023 Jun 5;254:115331. doi: 10.1016/j.ejmech.2023.115331. Epub 2023 Apr 7.
PI3Kδ is a lipid kinase which plays a key role in airway inflammatory conditions. Accordingly, the inhibition of PI3Kδ can be considered a valuable strategy for the treatment of chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD). In this work, we describe our efforts to identify new PI3Kδ inhibitors following an "inhalation by design" strategy. Starting from the identification of a purine scaffold, we carried out a preliminary SAR expansion which led to the identification of a new hit characterized by a high enzymatic potency and moderate PI3Kδ selectivity. A subsequent optimization led to novel purine based derivatives with favorable in vitro ADME profiles, which might represent promising starting points for future development of new inhaled drug candidates.
PI3Kδ 是一种脂质激酶，在气道炎症条件中发挥关键作用。因此，抑制 PI3Kδ 可以被认为是治疗哮喘和慢性阻塞性肺疾病（COPD）等慢性呼吸道疾病的一种有价值的策略。在这项工作中，我们描述了我们根据“吸入设计”策略来识别新型 PI3Kδ 抑制剂的努力。从鉴定嘌呤支架开始，我们进行了初步的 SAR 扩展，从而鉴定出一种新型的高酶活性和中等 PI3Kδ 选择性的新型命中化合物。随后的优化导致了具有有利的体外 ADME 特性的新型嘌呤衍生物，这可能代表了未来开发新型吸入药物候选物的有希望的起点。
