The Discovery of 7‑Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)‑N‑(6-methylpyrazolo[1,5‑a]pyrimidin-3-yl)imidazo[1,2‑a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke

Interleukin receptor-associated kinase 4 (IRAK4) is a
key node of signaling within the innate immune system that regulates
the production of inflammatory cytokines and chemokines. The presence
of damage-associated molecular patterns (DAMPs) after tissue damage such as
stroke or traumatic brain injury (TBI) initiates signaling through
the IRAK4 pathway that can lead to a feed-forward inflammatory loop
that can ultimately hinder patient recovery. Herein, we describe the
first potent, selective, and CNS-penetrant IRAK4 inhibitors for the
treatment of neuroinflammation. Lead compounds from the series were
evaluated in CNS PK/PD models of inflammation, as well as a mouse
model of ischemic stroke. The SAR optimization detailed within culminates
in the discovery of BIO-7488, a highly selective and potent IRAK4
inhibitor that is CNS penetrant and has excellent ADME properties.

白介素受体相关激酶4（IRAK4）是先天免疫系统中调控炎症细胞因子和趋化因子产生的关键节点。组织损伤如中风或颅脑外伤（TBI）后出现的损伤相关分子模式（DAMPs）的存在，通过IRAK4通路启动信号传导，可能导致正向炎症回路，最终阻碍患者康复。本研究中，我们描述了首个高效、选择性及脑部渗透性强的IRAK4抑制剂，用于治疗神经炎症。系列先导化合物在炎症的大脑PK/PD模型中进行了评估，并在缺血性中风小鼠模型中进行了测试。文中详细描述的SAR优化最终导致了BIO-7488的发现，这是一种高度选择性、强效的IRAK4抑制剂，具有优异的脑部渗透性和良好的药代动力学/药效学特性。