Tolkacheva Elena V, Saliev Alexandr Yu, Salakhov Tagir L, Balakin Konstantin V, Ivanov Roman A, Chernyshov Vladimir V
Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy ave. 1, Sirius, Krasnodar Region, 354340, Russia.
Moscow Institute of Physics and Technology Department of Innovative Pharmaceuticals, Medical Technology and Biotechnology Moscow Russia.
Curr Med Chem. 2025 Aug 26. doi: 10.2174/0109298673366258250710101146.
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.
This review summarizes "next-in-class" GLP-1 receptor agonists developed, identifying different relationships between the molecular structure and functional activity of agonists.
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.
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 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.
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.
