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

Zheng, Lei1; Chen, Kun1; Xie, Yifan1; Xia, Chuang1; Bao, Ying-Xia5; Bi, Huichang1; Wang, Jigang1,2,3,4,6; Zhou, Zhong-Zhen1

2024-11-05

10.1016/j.ejmech.2024.116710

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY   影响因子和分区

0223-5234

1768-3254

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.

Indazole derivatives PDE4 inhibitors Inflammatory bowel disease Safety profiles

SCI

英语

通讯

Foundation for the National Natural Science Foundation of China[81872735] ; National Natural Science Foundation of China[U23A20535] ; Natural Science Foundation of Guangdong Province[2024A1515011307] ; Science and Technology Program of Guangdong Province of China[2023A0505030012]

Pharmacology & Pharmacy

Chemistry, Medicinal

WOS:001288999100001

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

CHEMISTRY

Web of Science

1.Southern Med Univ, Innovat Program Drug Res Neurol & Metab Dis, NMPA Key Lab Res & Evaluat Drug Metab, Guangdong Prov Key Lab New Drug Screening,Guangdon, Guangzhou 510515, Peoples R China
2.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Dept Urol, Shenzhen 518020, Guangdong, Peoples R China
3.China Acad Chinese Med Sci, Artemisinin Res Ctr, State Key Lab Qual Ensurance & Sustainable Use Dao, Beijing 100700, Peoples R China
4.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China
5.Guangzhou Baiyunshan Pharmaceut Co Ltd, Guangzhou Baiyunshan Pharmaceut Gen Factory, Guangzhou, Peoples R China
6.Southern Med Univ, NMPA Key Lab Res & Evaluat Drug Metab, Guangdong Prov Key Lab New Drug Screening, Guangdong Hongkong Macao Joint Lab New Drug Screen, Guangzhou 510515, Peoples R China

Zheng, Lei,Chen, Kun,Xie, Yifan,et al. Discovery of novel N2-indazole derivatives as phosphodiesterase 4 inhibitors for the treatment of inflammatory bowel disease[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,277.

Zheng, Lei.,Chen, Kun.,Xie, Yifan.,Xia, Chuang.,Bao, Ying-Xia.,...&Zhou, Zhong-Zhen.(2024).Discovery of novel N2-indazole derivatives as phosphodiesterase 4 inhibitors for the treatment of inflammatory bowel disease.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,277.

Zheng, Lei,et al."Discovery of novel N2-indazole derivatives as phosphodiesterase 4 inhibitors for the treatment of inflammatory bowel disease".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 277(2024).