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

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...

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Bibliographic Details
Authors: 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
Format: article
Publication Date:2022
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18796
Online Access:http://hdl.handle.net/20.500.12105/18796
Access Level:Open access
Keyword:Administration, Oral
Animals
Diabetes Mellitus, Type 2
Glucagon-Like Peptide-1 Receptor
Obesity
Peptides
Description
Summary: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.

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