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）亚型是炎症性疾病（如类风湿性关节炎（RA）和牛皮癣）以及肝癌的一种新型，有希望的治疗靶标。阿₃ AR被耦合到抑制腺苷酸环化酶和丝裂原活化蛋白激酶（MAPK）途径的调节，导致转录的调节。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。众多A ₃已经报道了AR激动剂，部分激动剂，拮抗剂和变构调节剂，并且研究了它们的结构-活性关系（SAR），最终形成了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。尽管种类差异很大，但已发现不同种类的杂环作为选择性的A ₃ AR阻滞剂。因此，由于进行了大量的基础研究工作，A _3的发展前景用于人类治疗的AR调节剂令人鼓舞。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均发现它们安全且耐受性良好，并显示出令人鼓舞的结果，尤其是在牛皮癣和RA中，其中A ₃ AR既是有希望的治疗靶点，又是生物学预测标记，这表明了个性化的医学治疗方法。瞄准A ₃ AR可能为受到炎性疾病，癌症和其他疾病影响的患者群体的安全有效治疗铺平道路。