Decara, Juan MVázquez-Villa, HenarBrea, JoséAlonso, MónicaSrivastava, Raj KamalOrio, LauraAlén, FranciscoSuárez, JuanBaixeras, ElenaGarcía-Cárceles, JavierEscobar-Peña, AndreaLutz, BeatRodríguez, RamónCodesido, EvaGarcia-Ladona, F JavierBennett, Teresa ABallesteros, Juan ACruces, JacoboLoza, María IBenhamú, BellindaRodríguez de Fonseca, FernandoLópez-Rodríguez, María L2024-02-272024-02-272022-03-29http://hdl.handle.net/10668/22590http://hdl.handle.net/20.500.12105/18796Peptidic 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.engVoRhttp://creativecommons.org/licenses/by/4.0/Administration, OralAnimalsDiabetes Mellitus, Type 2Glucagon-Like Peptide-1 ReceptorObesityPeptidesAttribution 4.0 International353492616575449-546110.1021/acs.jmedchem.1c018421520-4804Journal of medicinal chemistryopen access