Details

Autor(en) / Beteiligte

• Decara, Juan M
• Vázquez-Villa, Henar
• Brea, José
• Alonso, Mónica
• Srivastava, Raj Kamal
• Orio, Laura
• Alén, Francisco
• Suárez, Juan
• Baixeras, Elena
• García-Cárceles, Javier
• Escobar-Peña, Andrea
• Lutz, Beat
• Rodríguez, Ramón
• Codesido, Eva
• Garcia-Ladona, F. Javier
• Bennett, Teresa A
• Ballesteros, Juan A
• Cruces, Jacobo
• Loza, María I
• Benhamú, Bellinda
• Rodríguez de Fonseca, Fernando
• López-Rodríguez, María L

Titel

Discovery of V‑0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide‑1 Receptor toward Oral Treatment for “Diabesity”

Ist Teil von

• Journal of medicinal chemistry, 2022-04, Vol.65 (7), p.5449-5461

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in the therapy of type-2 diabetes and are being considered for reducing food intake in obesity. Potential advantages of small molecules acting as positive allosteric modulators (PAMs) of GLP-1R, including oral administration and reduced unwanted effects, could improve the utility of this class of drugs. Here, we describe the discovery of compound 9 (4-{[1-({3-[4-(trifluoromethyl)­phenyl]-1,2,4-oxadiazol-5-yl}­methyl)­piperidin-3-yl]­methyl}­morpholine, V-0219) that exhibits enhanced efficacy of GLP-1R stimulation, subnanomolar potency in the potentiation of insulin secretion, and no significant off-target activities. The identified GLP-1R PAM shows a remarkable in vivo activity, reducing food intake and improving glucose handling in normal and diabetic rodents. Enantioselective synthesis revealed oral efficacy for (S)-9 in animal models. Compound 9 behavior bolsters the interest of a small-molecule PAM of GLP-1R as a promising therapeutic approach for the increasingly prevalent obesity-associated diabetes.