Lazewska Dorota, Kiec-Kononowicz Katarzyna
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Krakow, Poland.
Front Biosci (Schol Ed). 2012 Jan 1;4(3):967-87. doi: 10.2741/s312.
Since 2000, when the histamine H4 receptor (H4R) was cloned, it has constituted an interesting target for drug development. Pharmacological studies suggest the potential utility of histamine H4R antagonists/inverse agonists in the treatment of inflammatory diseases, e.g. allergic rhinitis, asthma, atopic dermatitis, colitis, or pruritus. The first H4R ligands were non-selective compounds, but intensive chemical and pharmacological work has led to the discovery of highly potent and selective H4R antagonists (e.g. JNJ7777120, CZC-13788, PF-2988403, A-940894, A-987306). The first compound (UR-63325) has finally entered into clinical studies for the treatment of allergic respiratory diseases (completing the phase I ascending dose trial) and has been found to be safe and well tolerated. The number of scientific publications and patent applications in the H4 field is increasing annually. Among the diverse chemical structures of the H4R antagonists described a 2-aminopyrimidine scaffold is repeatedly found. This review looked at recent advances in the search for H4R antagonists as reflected in patent applications/patents and peer-reviewed publications over the last two years. The work concerns azines (mono-, di-, triazines) and their fused analogues. The chemistry and pharmacology has been described.
自2000年组胺H4受体（H4R）被克隆以来，它一直是药物研发的一个有趣靶点。药理学研究表明，组胺H4R拮抗剂/反向激动剂在治疗炎症性疾病（如过敏性鼻炎、哮喘、特应性皮炎、结肠炎或瘙痒症）方面具有潜在效用。首批H4R配体是非选择性化合物，但经过深入的化学和药理学研究，已发现了高效且选择性的H4R拮抗剂（如JNJ7777120、CZC-13788、PF-2988403、A-940894、A-987306）。首个化合物（UR-63325）最终已进入治疗过敏性呼吸道疾病的临床研究（已完成I期递增剂量试验），且已证明其安全且耐受性良好。H4领域的科学出版物和专利申请数量每年都在增加。在所描述的H4R拮抗剂的多种化学结构中，反复发现了一种2-氨基嘧啶骨架。本综述着眼于过去两年专利申请/专利及同行评审出版物中所反映的H4R拮抗剂研究的最新进展。这项工作涉及嗪类（单嗪、二嗪、三嗪）及其稠合类似物。已对其化学和药理学进行了描述。
