Tichenor Mark S, Thurmond Robin L, Venable Jennifer D, Savall Brad M
Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
J Med Chem. 2015 Sep 24;58(18):7119-27. doi: 10.1021/acs.jmedchem.5b00516. Epub 2015 Jun 3.
Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.
组胺是一种重要的内源性信号分子，参与多种生理过程，包括过敏反应、胃酸分泌、神经递质释放和炎症。组胺的生物学效应由四种具有不同功能和分布模式的组胺受体（H1-H4）介导。最近发现的组胺受体（H4）已成为治疗炎症性疾病的一个有前景的药物靶点。对H4受体在人类疾病中的作用的详细了解仍然难以捉摸，部分原因是人类和啮齿动物H4受体之间的低序列相似性使临床前药理学向人类的转化变得复杂。本综述概述了研究跨物种构效关系的H4药物发现计划，重点关注已进入过敏、特应性皮炎、哮喘和类风湿关节炎临床研究的2-氨基嘧啶化学类型的功能分析。
