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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Detalles Bibliográficos
Autores: Decara, Juan M., Vázquez Villa, María Del Henar, Brea, José, Alonso, Mónica, Srivastava, Raj Kamal, Orio Ortiz, Laura, Alén Fariñas, Francisco, Suárez, Juan, Baixeras, Elena, García Cárceles, Javier, Escobar Peña, Ana Andrea, Lutz, Beat, Rodríguez, Ramón, Codesido, Eva, Garcia Ladona, F. Javier, Bennett, Teresa A., Ballesteros, Juan A., Cruces, Jacobo, Loza, María I., Benhamú Salama, Bellinda, Rodríguez De Fonseca, Fernando Antonio, López Rodríguez, María Luz
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/71661
Acceso en línea:https://hdl.handle.net/20.500.14352/71661
Access Level:acceso abierto
Palabra clave:547
Química orgánica (Química)
2306 Química Orgánica
Descripción
Sumario: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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