ArticleCurrent medicinal chemistry2025
"Next-in-class" GLP-1R Danuglipron- and Lotiglipron-like Agonists: A Patent Review (2020-2024).
Article in Current medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers, 1 of them a synthesis that pooled it.
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Who cites it
3 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Investigation into the efficacy and safety profile of oral small-molecule GLP-1 receptor agonists in type 2 diabetes and obesity: a systematic review and meta-analysis.Frontiers in endocrinology · 2026Pooled it
- Renal Effects of Glucagon-like Peptide-1 Receptor Agonists in Diabetic Kidney Disease: A Narrative Review of Mechanisms and Clinical Evidence.Medicina (Kaunas, Lithuania) · 2026Review
- Novel Small Molecule GLP-1R Agonists Based on 1Molecules (Basel, Switzerland) · 2026Article
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGLP-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.
objectiveThis review summarizes "next-in-class" GLP-1 receptor agonists developed, identifying different relationships between the molecular structure and functional activity of agonists.
methodsPatents 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.
resultsOur 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 1H-benzo[d]imidazole nucleus or (S)-oxetan-2-ylmethyl substituent in the prototype structure with bioisosteric heterocycles, may be viable approaches. The replacement of 1,4-disubstituted piperidine linked with its (S)-2-methyl-substituted homologue or O, N-disubstituted piperidin-4-ol may also result in highly potent agonists. Additionally, the classic 2,4-EWG-disubstituted benzyl alcohol residue allows significant variability.
conclusionDespite 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.
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40873282What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.