Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.

中文翻译：

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BIO-8169 的发现─一种用于治疗神经炎症的高效、选择性、脑渗透性 IRAK4 抑制剂


白细胞介素受体相关激酶 4 (IRAK4) 在通过 Toll 样和白细胞介素 1 受体的先天免疫信号传导中发挥重要作用，是治疗炎症性疾病和癌症的一个有吸引力的靶点。我们之前报道了强效、选择性和脑渗透性咪唑并嘧啶系列 IRAK4 抑制剂的开发。然而，先导分子 BIO-7488 (1) 溶解度低，导致 PK 变化、化合物积累和体内耐受性差。在此，我们描述了一系列具有改善的溶解度的吡啶酮类似物的发现，这些类似物具有高效、选择性并表现出理想的 PK 特性，包括良好的口服生物利用度和出色的脑渗透性。 BIO-8169 (2) 减少体内促炎细胞因子的产生，在啮齿类动物和狗的安全性研究中具有良好的耐受性，其边缘远高于预测的有效暴露量，并且在多发性硬化症小鼠模型中显示出有希望的结果。