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
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.
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.
