Glucagon-like peptide-1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. The development of orally bioavailable and long-acting small-molecule GLP-1R agonists is a pursuit in both academia and industry. Herein, new selenium (Se)-containing compounds were designed using a Se-oxygen bioisostere strategy on the danuglipron scaffold. Among these, compound was orally bioavailable and exhibited full agonistic efficacy in promoting cyclic adenosine monophosphate (cAMP) accumulation. In hGLP-1R knock-in mice, effectively reduced blood glucose levels and food intake, with the duration of action slightly extended compared to that of danuglipron. Importantly, no significant adverse effects were observed in mice treated with during the subacute toxicity studies. This study delineates the potential of Se-containing compounds as orally bioavailable GLP-1R agonists, with compound emerging as a promising candidate for T2DM and obesity treatment.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.4c02616 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of Selenium-Containing Derivatives as Potent and Orally Bioavailable GLP-1R Agonists.
J Med Chem
January 2025
Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Glucagon-like peptide-1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. The development of orally bioavailable and long-acting small-molecule GLP-1R agonists is a pursuit in both academia and industry. Herein, new selenium (Se)-containing compounds were designed using a Se-oxygen bioisostere strategy on the danuglipron scaffold.
View Article and Find Full Text PDFPediatric Formulation Optimization Using a Rational Design: Exploring Amorphous Solid Dispersion Technology with Terbinafine Hydrochloride as a Case Study.
AAPS PharmSciTech
January 2025
Department of Chemistry, Center for Physical and Mathematical Sciences, Federal University of Santa Catarina, Florianópolis, SC, 88040-900, Brazil.
Developing orally administered pediatric formulations presents significant challenges due to the unique characteristics of pediatric patients. Terbinafine hydrochloride (TER), a powerful antifungal agent, is effective against various fungal infections, including Tinea capitis, which is common in children. However, its low aqueous solubility necessitates innovative pharmaceutical strategies to enhance its effectiveness.
View Article and Find Full Text PDFSafe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia.
ACS Pharmacol Transl Sci
January 2025
Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
The accumulation of ceramides and related metabolites has emerged as a pivotal mechanism contributing to the onset of age-related diseases. However, small molecule inhibitors targeting the ceramide synthesis pathway for clinical use are currently unavailable. We synthesized a safe and orally bioavailable inhibitor, termed ALT-007, targeting the rate-limiting enzyme of ceramide synthesis, serine palmitoyltransferase (SPT).
View Article and Find Full Text PDFCemdomespib Therapy Slows the Progression of Neuromuscular Weakness and Demyelination in the R75W-Connexin 32 Animal Model of Charcot-Marie-Tooth 1X Disease.
ACS Pharmacol Transl Sci
January 2025
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045, United States.
Mutations in connexin 32 (Cx32) are a common cause of Charcot-Marie-Tooth 1X (CMT1X) disease, an inherited peripheral neuropathy characterized by progressive neuromuscular weakness and demyelination. There are no approved pharmacologic therapies for CMT1X, and identifying new treatments that slow the onset and severity of neuromuscular decline may aid disease management. Cemdomespib is an orally bioavailable small molecule that improved demyelination and neuromuscular junction (NMJ) morphology in mice lacking Cx32 expression.
View Article and Find Full Text PDFStrategies to Enhance Nanocrystal Formulations for Overcoming Physiological Barriers Across Diverse Routes of Administration.
Int J Nanomedicine
January 2025
Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, 72079, USA.
Poor aqueous solubility and bioavailability limit the translation of new drug candidates into clinical applications. Nanocrystal formulations offer a promising approach for improving the dissolution rate and saturation solubility. These formulations are applicable for various routes of administration, with each presenting unique opportunities and challenges posed by the physiological barriers.
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!