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,Journal of Medicinal Chemistry

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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-11 , DOI: 10.1021/acs.jmedchem.3c02226
Ryan Evans ₁ , Philippe N Bolduc ₁ , Magnus Pfaffenbach ₁ , Fang Gao ₁ , Tricia May-Dracka ₁ , Terry Fang ₂ , Brian T Hopkins ₁ , Jayanth V Chodaparambil ₃ , Kate L Henry ₂ , Pei Li ₄ , Claire Metrick ₃ , Ashley Nelson ₂ , Patrick Trapa ₄ , Ankur Thomas ₂ , Linda Burkly ₂ , Emily A Peterson ₁

Affiliation

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.

中文翻译：

7-异丙氧基-2-(1-甲基-2-氧杂双环[2.1.1]己-4-基)-N-(6-甲基吡唑并[1,5-a]嘧啶-3-基)咪唑的发现[ 1,2-a]pyrimidine-6-carboxamide (BIO-7488)，一种有效的、选择性的、中枢神经系统渗透性的 IRAK4 抑制剂，用于治疗缺血性中风

白细胞介素受体相关激酶 4 (IRAK4) 是先天免疫系统内信号传导的关键节点，可调节炎症细胞因子和趋化因子的产生。中风或创伤性脑损伤 (TBI) 等组织损伤后，损伤相关分子模式(DAMP) 的存在会通过 IRAK4 途径启动信号传导，从而导致前馈炎症循环，最终阻碍患者康复。在此，我们描述了第一个用于治疗神经炎症的有效、选择性和中枢神经系统渗透性 IRAK4 抑制剂。该系列的先导化合物在 CNS PK/PD 炎症模型以及缺血性中风小鼠模型中进行了评估。其中详细介绍的 SAR 优化最终导致 BIO-7488 的发现，这是一种高度选择性和有效的 IRAK4 抑制剂，具有 CNS 渗透性并具有优异的 ADME 特性。

更新日期：2024-03-11

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