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"Next-in-class" GLP-1R Danuglipron- and Lotiglipron-like Agonists: A Patent Review (2020-2024)
Elena V Tolkacheva1, Alexandr Yu Saliev1, Tagir L Salakhov1
1Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy ave. 1, Sirius, Krasnodar Region, 354340, Russia.
Current Medicinal Chemistry
|August 28, 2025
Summary
Next-generation oral glucagon-like peptide-1 (GLP-1) receptor agonists show promise for type 2 diabetes and obesity. Structural modifications reveal key trends for developing highly potent small-molecule GLP-1R agonists.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Discovery
Background:
- Glucagon-like peptide-1 (GLP-1) receptor agonists have transformed type 2 diabetes and obesity treatment, primarily via injectable therapies.
- Small-molecule GLP-1 receptor agonists offer oral administration but lack clinical establishment.
- Pfizer's danuglipron and lotiglipron pioneered "first-in-class" oral GLP-1R agonists, serving as prototypes for subsequent drug development.
Purpose of the Study:
- To review "next-in-class" GLP-1 receptor agonists.
- To identify structure-activity relationships (SAR) for novel oral GLP-1R agonists.
- To explore chemical modifications for improved agonist potency and properties.
Main Methods:
- Patent literature analysis from January 2021 to July 2024.
- Searched databases like Espacenet and Google Patents for danuglipron- and lotiglipron-like agonists.
- Analyzed over 5,000 compounds from 67 patent publications.
Main Results:
- Key SAR trends identified for potent oral GLP-1R agonists.
- Carboxyl group presence enhances activity; bioisosteric replacement may improve ADME.
- Modifications including privileged fragments, heterocycle replacements, and novel piperidine derivatives show potential.
- Variability exists in the 2,4-EWG-disubstituted benzyl alcohol residue.
Conclusions:
- Despite early challenges with danuglipron and lotiglipron, research into oral GLP-1R agonists is advancing.
- Novel chemotypes demonstrate high potency, suggesting potential for future approved therapies.
- Further development may overcome complexities of GLP-1 receptor signaling for oral administration.
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