2026-06-14T14:34:13Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/187962024-09-21T20:03:30Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927

00925njm 22002777a 4500 dc Decara, Juan M author Vázquez-Villa, Henar author Brea, José author Alonso, Mónica author Srivastava, Raj Kamal author Orio, Laura author Alén, Francisco author Suárez, Juan author Baixeras, Elena author García-Cárceles, Javier author Escobar-Peña, Andrea author Lutz, Beat author Rodríguez, Ramón author Codesido, Eva author Garcia-Ladona, F Javier author Bennett, Teresa A author Ballesteros, Juan A author Cruces, Jacobo author Loza, María I author Benhamú, Bellinda author Rodríguez de Fonseca, Fernando author López-Rodríguez, María L author 2022-03-29 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. 10.1021/acs.jmedchem.1c01842 1520-4804 Journal of medicinal chemistry http://hdl.handle.net/10668/22590 35349261 http://hdl.handle.net/20.500.12105/18796 Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity".