In 2020, the anti-tumor necrosis factor (TNF) monoclonal antibody Humira® generated US$165.8 billion in cumulative sales and snatched the crown for the industry’s most successful drug from Lipitor (atorvastatin). TNF-α is a major component in beneficial and disease-related inflammation and TNF-α-inhibitor biologics have gained widespread use in autoimmune diseases, such as rheumatoid arthritis (RA). Many more diseases could benefit from TNF-α inhibitors, such as Alzheimer’s disease (AD) or major depression. However, the nature of TNF-α-inhibitor biologics prohibits central nervous system (CNS) applications. Moreover, high drug production costs and pricing, together with antidrug immune reactions and insufficient patient coverage, argue for the development of small-molecule drugs. Recently, drug-like orally available small molecules were described with high activity in animal disease models with activities comparable to those of antibodies.

2020年，抗肿瘤坏死因子（TNF）单克隆抗体修美乐®累计销售额达1658亿美元，夺取立普妥（阿托伐他汀）行业最成功药物桂冠。TNF-α 是有益和疾病相关炎症的主要成分，TNF-α 抑制剂生物制剂已广泛用于自身免疫性疾病，如类风湿性关节炎 (RA)。更多疾病可以从 TNF-α 抑制剂中受益，例如阿尔茨海默病 (AD) 或重度抑郁症。然而，TNF-α 抑制剂生物制剂的性质阻碍了中枢神经系统 (CNS) 的应用。此外，高昂的药物生产成本和定价，以及抗药物免疫反应和患者覆盖面不足，都在推动小分子药物的开发。最近，