2. Academic Validation
  3. Discovery of novel N2-indazole derivatives as phosphodiesterase 4 inhibitors for the treatment of inflammatory bowel disease

Discovery of novel N2-indazole derivatives as phosphodiesterase 4 inhibitors for the treatment of inflammatory bowel disease

  • Eur J Med Chem. 2024 Jul 31:277:116710. doi: 10.1016/j.ejmech.2024.116710.
Lei Zheng 1,  Kun Chen 1,  Yifan Xie 1,  Jiaxi Huang 1,  Chuang Xia 1,  Ying-Xia Bao 2,  Huichang Bi 1,  Jigang Wang 3,  Zhong-Zhen Zhou 4
Affiliations

Affiliations

  • 1 Innovation Program of Drug Research on Neurological and Metabolic Diseases, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Guangzhou Baiyunshan Pharmaceutical Co. Ltd., Guangzhou Baiyunshan Pharmaceutical General Factory, Guangzhou, China.
  • 3 Innovation Program of Drug Research on Neurological and Metabolic Diseases, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Department of Urology, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, Guangdong, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China. Electronic address: jgwang@icmm.ac.cn.
  • 4 Innovation Program of Drug Research on Neurological and Metabolic Diseases, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: zhouzz@smu.edu.cn.
PMID: 39098133 DOI: 10.1016/j.ejmech.2024.116710
Abstract

Inflammatory bowel disease (IBD) is a chronic and progressive condition with a significant global burden. Currently, available treatments primarily provide symptomatic relief and retard disease progression, yet they do not offer a cure and are frequently associated with adverse effects. Therefore, the discovery of new targets and therapeutic drugs for IBD is crucial. Phosphodiesterase 4 (PDE4) inhibitors have emerged as promising candidates in the search for effective IBD treatments, although dose-dependent side effects hamper their clinical utility. In this study, building upon heterocyclic biaryl derivatives (TPA16), we designed and synthesized a series of N2-substituted indazole-based PDE4D inhibitors, emphasizing improving safety profiles. An Enzyme activity screening discovered an optimized compound, LZ-14 (Z21115), which exhibited high PDE4D7 (IC50 = 10.5 nM) inhibitory activity and good selectivity. More interestingly, LZ-14 has demonstrated promising effects in treating IBD in mouse models by improving the inflammatory response and colon injury. Furthermore, LZ-14 displayed low emetogenic potential in ketamine/xylazine anesthesia mice alternative models.

Keywords

Indazole derivatives; Inflammatory bowel disease; PDE4 inhibitors; Safety profiles.

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