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Discovery of the novel and potent histamine H1 receptor antagonists for treatment of allergic diseases.
Chu, Zhaoxing; Cen, Lifang; Xu, Qinlong; Lin, Gaofeng; Mo, Jiajia; Shao, Li; Zhao, Yan; Li, Jiaming; Ye, Wenfeng; Fang, Tao; Ren, Weijie; Zhu, Qihua; He, Guangwei; Xu, Yungen.
Afiliación
  • Chu Z; 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.
  • Cen L; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
  • Xu Q; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • Lin G; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • Mo J; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • Shao L; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • Zhao Y; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • Li J; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • Ye W; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • Fang T; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • Ren W; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
  • Zhu Q; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: zhuqihua@vip.126.com.
  • He G; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China. Electronic address: hgwhipi@hotmail.com.
  • Xu Y; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xyg@cpu.edu.cn.
Eur J Med Chem ; 268: 116197, 2024 Mar 15.
Article en En | MEDLINE | ID: mdl-38368709
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Loratadina / Antagonistas de los Receptores Histamínicos H1 / Hipersensibilidad Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Loratadina / Antagonistas de los Receptores Histamínicos H1 / Hipersensibilidad Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article