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Synfacts 2022; 18(09): 1025
DOI: 10.1055/s-0041-1738304
Innovative Drug Discovery and Development

Synthesis of Danuglipron: An Orally Available GLP-1R Agonist

Contributor(s):
Antonia F. Stepan (Roche)
,
Ferdinand H. Lutter (Janssen Pharmaceutica)
Griffith DA, *, Edmonds DJ, Fortin J.-P, Kalgutkar AS, Kuzmiski JB, Loria PM, Saxena AR, Bagley SW, Buckeridge C, Curto JM, Derksen DR, Dias JM, Griffor MC, Han S, Jackson VM, Landis MS, Lettiere D, Limberakis C, Liu Y, Mathiowetz AM, Patel JC, Piotrowski DW, Price DA, Ruggeri RB, Tess DA. Pfizer Worldwide Research, Development, and Medical, Cambridge, USA
A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide‑1 Receptor.

J. Med. Chem. 2022;
65: 8208-8226
DOI: 10.1021/acs.jmedchem.1c01856.
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Key words

danuglipron - Buchwald–Hartwig etherification - benzimidazoles - chemoselective saponification - antidiabetics - PF-06882961

Significance

The glucagon-like peptide-1 receptor (GLP-1R) is a well-known target, playing a key role in metabolic health. Peptidic agonists have been approved for the treatment of type 2 diabetes and obesity. Danuglipron is the first orally available small-molecule GLP-1R agonist showing to decrease glucose levels in humans. A phase 1 clinical study has recently been completed.


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Comment

A transformation of interest in the synthesis of danuglipron is the saponification of the methyl ester J to the corresponding acid in the penultimate step of the synthesis. Extensive evaluation of various conditions revealed that TBD is a suitable base for the chemoselective production of the acid without hydrolysis of the nitrile moiety.


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Publication History

Article published online:
18 August 2022

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