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

• Published in: European journal of medicinal chemistry 2024-11, Vol.277, p.116710, Article 116710
• Main Authors: Zheng, Lei, Chen, Kun, Xie, Yifan, Huang, Jiaxi, Xia, Chuang, Bao, Ying-Xia, Bi, Huichang, Wang, Jigang, Zhou, Zhong-Zhen
• Format: Article
• Language: English
• Subjects: Indazole derivatives; Inflammatory bowel disease; PDE4 inhibitors; Safety profiles
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116710

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. [Display omitted] •Thirty-six novel N2-indazole derivatives were designed and synthesized.•LZ-14 displayed satisfactory inhibitory activities against PDE4D.•LZ-14, with a high safety profile, showed low emetic potential.•LZ-14 was a potential novel agent for treating Inflammatory Bowel Diseases.