Decara, Juan M.Vázquez Villa, HenarBrea, JoséAlonso, MónicaSrivastava, Raj KamalOrio Ortiz, LauraAlen Fariñas, FranciscoSuárez, JuanBaixeras, ElenaGarcía Cárceles, JavierEscobar Peña, AndreaLutz, BeatRodríguez, RamónCodesido, EvaGarcia Ladona, F. JavierBennett, Teresa A.Ballesteros, Juan A.Cruces, JacoboLoza, María I.Benhamú Salama, BellindaRodríguez de Fonseca, FernandoLópez Rodríguez, María L.2023-06-222023-06-2220220022-262310.1021/acs.jmedchem.1c01842https://hdl.handle.net/20.500.14352/71661CRUE-CSIC (Acuerdos Transformativos 2022)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.engAtribución 3.0 Españajournal articlehttps://doi.org/10.1021/acs.jmedchem.1c01842open access547Química orgánica (Química)2306 Química Orgánica