Bruton's tyrosine kinase (BTK) plays a crucial role in adaptive and immune responses by modulating B-cell, Fc, toll-like, and chemokine receptor signaling pathways. BTK inhibition is a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. The development of novel, highly selective, and less toxic BTK inhibitors may be beneficial for the treatment of autoimmune diseases with unmet medical needs. In this study, structure-based drug design was used to discover a series of novel, potent, and selective covalent BTK inhibitors with a 1,4,5,6,8-pentaazaacenaphthylen scaffold. Among them, compound 36R exhibited high kinase selectivity, long target occupancy time, appropriate pharmacokinetic properties, and dose-dependent efficacy in a rat model of collagen-induced arthritis. Therefore, 36R is a novel BTK inhibitor requiring further development for the treatment of autoimmune diseases.

Bruton 酪氨酸激酶 (BTK) 通过调节 B 细胞、Fc、toll 样和趋化因子受体信号通路在适应性和免疫反应中起着至关重要的作用。BTK 抑制是一种很有前途的治疗炎症和自身免疫性疾病的方法。开发新型、高选择性和低毒性的 BTK 抑制剂可能有利于治疗未满足医疗需求的自身免疫性疾病。在这项研究中，基于结构的药物设计用于发现一系列具有 1,4,5,6,8-五氮杂苊骨架的新型、有效和选择性共价 BTK 抑制剂。其中，化合物36R在胶原诱导的关节炎大鼠模型中表现出高激酶选择性、长靶点占据时间、适当的药代动力学特性和剂量依赖性功效。因此，36R是一种新型的 BTK 抑制剂，需要进一步开发用于治疗自身免疫性疾病。