Thurmond Robin L, Venable Jennifer, Savall Brad, La David, Snook Sandra, Dunford Paul J, Edwards James P
Janssen Research & Development, LLC, San Diego, CA, 92121, USA.
Handb Exp Pharmacol. 2017;241:301-320. doi: 10.1007/164_2016_130.
The discovery of the histamine H receptor (HR) provided a new avenue for the exploration of the physiological role of histamine, as well as providing a new drug target for the development of novel antihistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the HR relative to other histamine receptors. The discovery of the selective HR antagonist JNJ 7777120 was vital for showing a role for the HR in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies. Further research let to the discovery of JNJ 39758979, which, similar to JNJ 7777120, was a potent and selective HR antagonist and showed anti-inflammatory and anti-pruritic activity preclinically. JNJ 39758979 advanced into human clinical studies and showed efficacy in reducing experimental pruritus and in patients with atopic dermatitis. However, development of this compound was terminated due to the occurrence of drug-induced agranulocytosis. This was overcome by developing another HR antagonist with a different chemical structure, toreforant, that does not appear to have this side effect. Toreforant has been tested in clinical studies in patients with rheumatoid arthritis, asthma, or psoriasis. In conclusions there have been many HR antagonists reported in the literature, but only a few have been studied in humans underscoring the difficulty in finding ligands with all of the properties necessary for testing in the clinic. Nevertheless, the clinical data to date suggests that HR antagonists can be beneficial in treating atopic dermatitis and pruritus.
组胺H受体（HR）的发现为探索组胺的生理作用提供了新途径，同时也为新型抗组胺药的研发提供了新的药物靶点。这一过程的第一步是鉴定选择性拮抗剂，以帮助阐明HR相对于其他组胺受体的药理学特性。选择性HR拮抗剂JNJ 7777120的发现对于揭示HR在炎症和瘙痒中的作用至关重要。虽然该化合物作为理解受体功能的工具非常成功，但它存在一些缺点，包括体内半衰期短以及在大鼠和狗中具有肾上腺皮质功能减退毒性，这使得它无法进入临床研究。进一步的研究发现了JNJ 39758979，它与JNJ 7777120类似，是一种强效且选择性的HR拮抗剂，在临床前显示出抗炎和抗瘙痒活性。JNJ 39758979进入了人体临床研究，并在减轻实验性瘙痒和特应性皮炎患者中显示出疗效。然而，由于药物诱导的粒细胞缺乏症的发生，该化合物的研发被终止。通过开发另一种具有不同化学结构的HR拮抗剂托瑞芬特克服了这一问题，托瑞芬特似乎没有这种副作用。托瑞芬特已在类风湿性关节炎、哮喘或银屑病患者的临床研究中进行了测试。总之，文献中报道了许多HR拮抗剂，但只有少数在人体中进行了研究，这突出了寻找具有临床测试所需所有特性的配体的困难。尽管如此，迄今为止的临床数据表明，HR拮抗剂在治疗特应性皮炎和瘙痒方面可能有益。
