Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhaled Administration

PI3Kδ
is a lipid kinase that is believed to be important
in the migration and activation of cells of the immune system. Inhibition
is hypothesized to provide a powerful yet selective immunomodulatory
effect that may be beneficial for the treatment of conditions such
as asthma or rheumatoid arthritis. In this work, we describe the identification
of inhibitors based on a thiazolopyridone core structure and their
subsequent optimization for inhalation. The initially identified compound
(13) had good potency and isoform selectivity but was
not suitable for inhalation. Addition of basic substituents to a region
of the molecule pointing to solvent was tolerated (enzyme inhibition
pIC50 > 9), and by careful manipulation of the pKa and lipophilicity, we were able to discover
compounds (20b, 20f) with good lung retention
and cell potency that could be taken forward to in vivo studies where
significant target engagement could be demonstrated.

PI3Kδ 是一种脂质激酶（lipid kinase），目前被认为在免疫系统细胞的迁移与活化过程中发挥关键作用。据推测，对其实施抑制可产生强效且具有选择性的免疫调节效应，有望为哮喘、类风湿关节炎等病症的治疗带来获益。本研究报道了一类以噻唑并吡啶酮（thiazolopyridone）为母核结构的抑制剂的发现历程，以及后续针对吸入给药的优化工作。最初筛选得到的化合物（13）虽具备良好的活性效力与亚型选择性，但不适用于吸入给药方案。在指向溶剂区域的分子位点引入碱性取代基后，该修饰可被良好耐受（酶抑制活性pIC50＞9）；通过精准调控pKa与脂溶性参数，我们最终获得了化合物（20b、20f），其兼具优异的肺滞留特性与细胞活性，可推进至体内研究阶段，并在该阶段中证实了显著的靶点结合效应。