Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
J Med Chem. 2021 Jun 24;64(12):8053-8075. doi: 10.1021/acs.jmedchem.1c00434. Epub 2021 Jun 3.
Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.
从我们之前描述的 PI3Kγ 抑制剂开始，我们描述了对结构-活性关系的探索，这些探索导致了发现高度有效的双 PI3Kγδ 抑制剂。我们探索了分子中两个位置的变化，包括大环化，但最终确定了一个更简单的系列，具有所需的效力谱，具有适合吸入的物理化学性质。我们能够在大鼠卵清蛋白挑战的变应性哮喘模型和源自哮喘患者的细胞中证明其疗效。优化的化合物 AZD8154 在肺部具有较长的作用持续时间，全身暴露量低，与针对非靶标的高选择性相结合。
