Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Artículo científico |
| Language: | en |
| Published: |
Journal of medicinal chemistry
2025
|
| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40167442/ |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1868266223129591808 |
|---|---|
| author | Miao, Lei Lou, Jinfang Xu, Sicong Zhang, Jinzhu Zhong, Yongqing Wang, Guojian Li, Yuanyuan Lei, Shaowei Shao, Shuai Wang, Jianghai Huang, Yun Tang, Xinyi Ding, Wanjing Ma, Zhongjun |
| author_facet | Miao, Lei Lou, Jinfang Xu, Sicong Zhang, Jinzhu Zhong, Yongqing Wang, Guojian Li, Yuanyuan Lei, Shaowei Shao, Shuai Wang, Jianghai Huang, Yun Tang, Xinyi Ding, Wanjing Ma, Zhongjun Miao, Lei Lou, Jinfang Xu, Sicong Zhang, Jinzhu Zhong, Yongqing Wang, Guojian Li, Yuanyuan Lei, Shaowei Shao, Shuai Wang, Jianghai Huang, Yun Tang, Xinyi Ding, Wanjing Ma, Zhongjun |
| collection | PubMed - marine biology |
| contents | Discovery of New Difluorocyclobutyl Derivatives as Effective Glucagon-Like Peptide-1 Receptor Agonists with Reduced hERG Inhibitory Activities. Miao, Lei Lou, Jinfang Xu, Sicong Zhang, Jinzhu Zhong, Yongqing Wang, Guojian Li, Yuanyuan Lei, Shaowei Shao, Shuai Wang, Jianghai Huang, Yun Tang, Xinyi Ding, Wanjing Ma, Zhongjun Animals Humans Male Mice Blood Glucose Cricetulus Drug Discovery ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptide-1 Receptor Agonists HEK293 Cells Hypoglycemic Agents Piperidines Structure-Activity Relationship Benzimidazoles Danuglipron (PF-06882961), a small-molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R) developed by Pfizer, has shown significant potential to reduce blood glucose levels and weight in patients with type 2 diabetes mellitus. However, it has moderate hERG inhibitory activities (IC = 4.3 μM), potentially conferring a risk for cardiac toxicity. Here, we report a new class of difluorocyclobutyl derivatives that can be used to reduce the potential hERG inhibition caused by the piperidine ring of danuglipron. After in vitro and in vivo screening, compound was found to be the most potent GLP-1R agonist, with an EC of 0.048 nM. Furthermore, compound showed preferable absorption and excellent β-arrestin pathway selectivity compared with danuglipron. In the glucose tolerance test, compound effectively inhibited elevated blood glucose levels. These results indicate that compound is a promising GLP-1R agonist. |
| format | Artículo científico |
| id | pubmed_40167442 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Journal of medicinal chemistry |
| record_format | pubmed |
| spellingShingle | Discovery of New Difluorocyclobutyl Derivatives as Effective Glucagon-Like Peptide-1 Receptor Agonists with Reduced hERG Inhibitory Activities. Miao, Lei Lou, Jinfang Xu, Sicong Zhang, Jinzhu Zhong, Yongqing Wang, Guojian Li, Yuanyuan Lei, Shaowei Shao, Shuai Wang, Jianghai Huang, Yun Tang, Xinyi Ding, Wanjing Ma, Zhongjun Animals Humans Male Mice Blood Glucose Cricetulus Drug Discovery ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptide-1 Receptor Agonists HEK293 Cells Hypoglycemic Agents Piperidines Structure-Activity Relationship Benzimidazoles Discovery of New Difluorocyclobutyl Derivatives as Effective Glucagon-Like Peptide-1 Receptor Agonists with Reduced hERG Inhibitory Activities. Miao, Lei Lou, Jinfang Xu, Sicong Zhang, Jinzhu Zhong, Yongqing Wang, Guojian Li, Yuanyuan Lei, Shaowei Shao, Shuai Wang, Jianghai Huang, Yun Tang, Xinyi Ding, Wanjing Ma, Zhongjun Animals Humans Male Mice Blood Glucose Cricetulus Drug Discovery ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptide-1 Receptor Agonists HEK293 Cells Hypoglycemic Agents Piperidines Structure-Activity Relationship Benzimidazoles Danuglipron (PF-06882961), a small-molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R) developed by Pfizer, has shown significant potential to reduce blood glucose levels and weight in patients with type 2 diabetes mellitus. However, it has moderate hERG inhibitory activities (IC = 4.3 μM), potentially conferring a risk for cardiac toxicity. Here, we report a new class of difluorocyclobutyl derivatives that can be used to reduce the potential hERG inhibition caused by the piperidine ring of danuglipron. After in vitro and in vivo screening, compound was found to be the most potent GLP-1R agonist, with an EC of 0.048 nM. Furthermore, compound showed preferable absorption and excellent β-arrestin pathway selectivity compared with danuglipron. In the glucose tolerance test, compound effectively inhibited elevated blood glucose levels. These results indicate that compound is a promising GLP-1R agonist. |
| title | Discovery of New Difluorocyclobutyl Derivatives as Effective Glucagon-Like Peptide-1 Receptor Agonists with Reduced hERG Inhibitory Activities. |
| topic | Animals Humans Male Mice Blood Glucose Cricetulus Drug Discovery ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptide-1 Receptor Agonists HEK293 Cells Hypoglycemic Agents Piperidines Structure-Activity Relationship Benzimidazoles |
| url | https://pubmed.ncbi.nlm.nih.gov/40167442/ |