Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma

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.

本研究基于此前报道的PI3Kγ抑制剂（PI3Kγ）展开，通过构效关系（structure–activity relationship）研究，成功开发出强效的双靶点PI3Kγδ抑制剂。我们对分子的两个位点进行了结构修饰，其中涵盖大环化（macrocyclization）策略，但最终筛选得到结构更简洁的化合物系列——该系列不仅具备预期的活性谱，还拥有适于吸入给药的适宜理化性质。我们在卵清蛋白诱导的过敏性哮喘大鼠模型以及哮喘患者来源的细胞中验证了该化合物的药效。经优化得到的化合物AZD8154在肺部具有长效作用，全身暴露量低，且对脱靶靶点（off-targets）具备优异的选择性。