2. Academic Validation
  3. Discovery of the novel and potent histamine H1 receptor antagonists for treatment of allergic diseases

Discovery of the novel and potent histamine H1 receptor antagonists for treatment of allergic diseases

  • Eur J Med Chem. 2024 Feb 3:268:116197. doi: 10.1016/j.ejmech.2024.116197.
Zhaoxing Chu 1,  Lifang Cen 2,  Qinlong Xu 3,  Gaofeng Lin 3,  Jiajia Mo 3,  Li Shao 3,  Yan Zhao 3,  Jiaming Li 4,  Wenfeng Ye 3,  Tao Fang 3,  Weijie Ren 2,  Qihua Zhu 5,  Guangwei He 6,  Yungen Xu 7
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • 4 College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 6 Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China. Electronic address: [email protected].
  • 7 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 38368709 DOI: 10.1016/j.ejmech.2024.116197
Abstract

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.

Keywords

Allergic diseases; Histamine H1 receptor antagonists; Muscarinic M3 receptor.

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