地氯雷他定
化学
组胺
组胺H1受体
赫尔格
药理学
组胺受体
IC50型
组胺H1拮抗剂
受体
体内
敌手
生物化学
内科学
体外
生物
钾通道
医学
生物技术
作者
Zhaoxing Chu,Lifang Cen,Qinlong Xu,Gaofeng Lin,Jiajia Mo,Shao Li,Yan Zhao,Jiaming Li,Wenfeng Ye,Tao Fang,Weijie Ren,Qihua Zhu,Guangwei He,Yungen Xu
标识
DOI:10.1016/j.ejmech.2024.116197
摘要
Desloratadine, a second-generation histamine H1 receptor antagonist, has established itself as a first-line drug for the treatment of allergic diseases. Despite its effectiveness, desloratadine exhibits an antagonistic effect on muscarinic M3 receptor, which can cause side effects such as dry mouth and urinary retention, ultimately limiting its clinical application. Herein, we describe the discovery of compound Ⅲ-4, a novel H1 receptor antagonist with significant H1 receptor antagonistic activity (IC50 = 24.12 nM) and enhanced selectivity towards peripheral H1 receptor. In particular, Ⅲ-4 exhibits reduced M3 receptor inhibitory potency (IC50 > 10,000 nM) and acceptable hERG inhibitory activity (17.6 ± 2.1 μM) compare with desloratadine. Additionally, Ⅲ-4 exhibits favorable pharmacokinetic properties, as well as in vivo efficacy and safety profiles. All of these reveal that Ⅲ-4 has potential to emerge as a novel H1 receptor antagonist for the treatment of allergic diseases. More importantly, the compound Ⅲ-4 (HY-078020) has recently been granted clinical approval.
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