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Abstract

Background

GLP-1 receptor peptide agonists have revolutionized type 2 diabetes mellitus and obesity treatment, primarily through injection-based therapies. Small-molecule GLP-1 receptor agonists allow oral administration, but none are clinically established. Pfizer's danuglipron and lotiglipron, presented in 2018-2019, were “first-in-class” drug candidates, becoming prototypes for “next-in-class” drug development.

Objective

This review summarizes “next-in-class” GLP-1 receptor agonists developed, identifying different relationships between the molecular structure and functional activity of agonists.

Methods

Patents containing danuglipron- and lotiglipron-like agonists from January 2021 to July 2024 were browsed in databases, such as Espacenet and Google Patents, using specified keywords. Over 5,000 compounds from 67 patent publications were analyzed.

Results

Our analysis identified some key general SAR trends. The presence of a carboxyl group leads to highly active agonists, but replacing it with bioisosteric analogs may improve the ADME profile of the target compounds. The introduction of specific privileged fragments, as well as the replacement of 1-benzo[]imidazole nucleus or ()-oxetan-2-ylmethyl substituent in the prototype structure with bioisosteric heterocycles, may be viable approaches. The replacement of 1,4-disubstituted piperidine linker with its ()-2-methyl-substituted homologue or , -disubstituted piperidin-4-ol may also result in highly potent agonists. Additionally, the classic 2,4-EWG-disubstituted benzyl alcohol residue allows significant variability.

Conclusion

Despite the limited clinical success of danuglipron and lotiglipron, as well as the inherent problems associated with the complex nature of GLP-1R signaling, the current state of research and the abundance of novel, promising chemotypes of highly potent compounds suggest that approved GLP-1R agonists may emerge in the coming years.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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/content/journals/cmc/10.2174/0109298673366258250710101146
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“Next-in-class” GLP-1R Danuglipron- and Lotiglipron-like Agonists: A Patent Review (2020-2024)
Bentham Science Publishers ; https://doi.org/10.2174/0109298673366258250710101146
/content/journals/cmc/10.2174/0109298673366258250710101146
/content/journals/cmc/10.2174/0109298673366258250710101146
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An Excel file containing: SMILES, the EC value, the patent number, and the compound number therein, ., for each of the “next in class” low molecular weight GLP-1 receptor agonists considered in this review. A Word file containing expanded versions of all Figures in this review, including a detailed disclosure of the substituents in each General Formula of this review. A Word file containing all Tables illustrating the key SAR trends discussed in the review. The TIFF and cdx files containing the structures of the most active GLP-1 receptor agonists from companies presented in this review. Supplementary material is available on the publisher’s website along with the published article.

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  • Article Type:     Review Article
Keywords: non-peptidyl oral agonists ; structure-activity relationship ; Type 2 diabetes mellitus ; small molecule agonists ; danuglipron ; glucagon-like peptide-1 receptor agonists ; lotiglipron ; next-in-class drugs

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