Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closely related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). In the best cases, we obtained a >50 fold selectivity for the hGluR over the hGIPR and a >1000 fold selectivity over the hGLP-1R. A potent and selective glucagon receptor antagonist was demonstrated to inhibit glucagon-induced glycogenolysis in primary rat hepatocytes as well as to lower glucagon-induced hyperglycemia in Sprague-Dawley rats. Furthermore, the compound was shown to lower blood glucose in the ob/ob mouse after oral dosing.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/jm7015599 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
New advances in novel pharmacotherapeutic candidates for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) between 2022 and 2024.
Acta Pharmacol Sin
January 2025
Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China.
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression.
View Article and Find Full Text PDFConsiderations for Perioperative Management Guidance Regarding GLP-1 Receptor Agonists: Evaluation of Current Practices and Future Directions.
Mil Med
January 2025
Department of Anesthesiology, Brooke Army Medical Center, Fort Sam Houston, TX 78234, USA.
Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become increasingly prevalent and have the potential to delay gastric emptying. The American Society of Anesthesiologists (ASA) released guidance regarding the perioperative management of patients receiving GLP-1 RAs, but it is unclear the extent to which hospitals in the U.S.
View Article and Find Full Text PDFBackground: Insulinoma is a neuroendocrine tumor, the main manifestation of which is hypoglycemia. However, the symptoms of hypoglycemia can be non-specific for a long time, especially outside provocative conditions, and quite often the tumor manifests from a life-threatening condition - hypoglycemic coma. In this regard, timely laboratory diagnosis of insulinoma and determination of its aggressive course is one of the priorities in modern researches.
View Article and Find Full Text PDFThe use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss in type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off target effects, including nausea and diarrhoea, remain a complication of using these agents, and modified versions with optimized pharmacological profiles and/or biased signaling at the cognate receptors are increasingly sought.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!