The A₃ adenosine receptor (A₃AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A₃AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen‐activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A₃AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A₃AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure–activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug‐like characteristics. The efficacy of nucleoside agonists may be suppressed to produce antagonists, by structural modification of the ribose moiety. Diverse classes of heterocycles have been discovered as selective A₃AR blockers, although with large species differences. Thus, as a result of intense basic research efforts, the outlook for development of A₃AR modulators for human therapeutics is encouraging. Two prototypical selective agonists, N6‐(3‐Iodobenzyl)adenosine‐5′‐N‐methyluronamide (IB‐MECA; CF101) and 2‐chloro‐N6‐(3‐iodobenzyl)‐adenosine‐5′‐N‐methyluronamide (Cl‐IB‐MECA; CF102), have progressed to advanced clinical trials. They were found safe and well tolerated in all preclinical and human clinical studies and showed promising results, particularly in psoriasis and RA, where the A₃AR is both a promising therapeutic target and a biologically predictive marker, suggesting a personalized medicine approach. Targeting the A₃AR may pave the way for safe and efficacious treatments for patient populations affected by inflammatory diseases, cancer, and other conditions.

中文翻译：

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A3 腺苷受体作为炎症调节剂：从药物化学到治疗


A ₃腺苷受体 (A ₃ AR) 亚型是一种新型、有前景的炎症性疾病治疗靶点，例如类风湿性关节炎 (RA) 和牛皮癣以及肝癌。 ₃ AR 与腺苷酸环化酶的抑制和丝裂原激活蛋白激酶 (MAPK) 途径的调节相结合，从而调节转录。此外，A ₃ AR影响几乎所有免疫细胞的功能和癌细胞的增殖。已经报道了许多 A ₃ AR 激动剂、部分激动剂、拮抗剂和变构调节剂，并对它们的构效关系 (SAR) 进行了研究，最终开发出具有药物样特征的有效和选择性分子。通过核糖部分的结构修饰，可以抑制核苷激动剂的功效以产生拮抗剂。不同类别的杂环化合物已被发现可作为选择性 A ₃ AR 阻断剂，但物种差异较大。因此，由于大量的基础研究工作，用于人类治疗的 A ₃ AR 调节剂的开发前景令人鼓舞。两种典型的选择性激动剂，N6-(3-碘苄基)腺苷-5′-N-甲基脲酰胺(IB-MECA；CF101)和2-氯-N6-(3-碘苄基)-腺苷-5′-N-甲基脲酰胺(Cl ‐IB-MECA；CF102)，已进入高级临床试验。在所有临床前和人类临床研究中，它们被发现是安全的且具有良好的耐受性，并显示出有希望的结果，特别是在银屑病和 RA 中，A ₃ AR 既是一个有前途的治疗靶点，又是一个生物预测标记，这表明了个性化医疗方法。 靶向 A ₃ AR 可能为受炎症性疾病、癌症和其他疾病影响的患者群体提供安全有效的治疗铺平道路。