Discovery of V-0219: a small-molecule positive allosteric modulator of the Glucagon-Like Peptide-1 Receptor toward oral treatment for “diabesity”

Decara del Olmo, Juan ManuelVázquez Villa, HenarBrea Floriani, José ManuelAlonso, MónicaSrivastava, Raj KamalOrio Ortiz, LauraAlén Fariñas, FranciscoSuárez Pérez, JuanBaixeras Llano, ElenaGarcía Cárceles, JavierEscobar Peña, AndreaLutz, BeatRodríguez, RamónCodesido, EvaGarcia Ladona, F. JavierBennett, Teresa A.Ballesteros, Juan A.Cruces, JacoboLoza García, María IsabelBenhamú Salama, BellindaRodríguez de Fonseca, FernandoLópez Rodríguez, María L.2026-01-142026-01-142022-03-29Juan M. Decara, Henar Vázquez-Villa, José Brea, Mónica Alonso, Raj Kamal Srivastava, Laura Orio, Francisco Alén, Juan Suárez, Elena Baixeras, Javier García-Cárceles, Andrea Escobar-Peña, Beat Lutz, Ramón Rodríguez, Eva Codesido, F. Javier Garcia-Ladona, Teresa A. Bennett, Juan A. Ballesteros, Jacobo Cruces, María I. Loza, Bellinda Benhamú, Fernando Rodríguez de Fonseca, and María L. López-Rodríguez Journal of Medicinal Chemistry 2022 65 (7), 5449-5461 DOI: 10.1021/acs.jmedchem.1c01842https://hdl.handle.net/10347/45118Peptidic 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 diabeteseng© 2022 American Chemical Society. This publication is licensed under CC-BY 4.0Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/CarbohydratesMixturesPeptides and proteinsRodent modelsSolutionsDiscovery of V-0219: a small-molecule positive allosteric modulator of the Glucagon-Like Peptide-1 Receptor toward oral treatment for “diabesity”journal article10.1021/acs.jmedchem.1c018420022-2623open access