2026-06-27T10:30:50Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/716612025-02-13T15:36:33Zcom_20.500.14352_14col_20.500.14352_15

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 2023-06-22T10:47:08Z 2023-06-22T10:47:08Z 2022 0022-2623 10.1021/acs.jmedchem.1c01842 https://hdl.handle.net/20.500.14352/71661 https://doi.org/10.1021/acs.jmedchem.1c01842 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. eng https://creativecommons.org/licenses/by/3.0/es/ open access Atribución 3.0 España Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for “Diabesity” journal article