%0 Journal Article
%A Decara, Juan M.
%A Vázquez Villa, María Del Henar
%A Brea, José
%A Alonso, Mónica
%A Srivastava, Raj Kamal
%A Orio Ortiz, Laura
%A Alén Fariñas, Francisco
%A Suárez, Juan
%A Baixeras, Elena
%A García Cárceles, Javier
%A Escobar Peña, Ana Andrea
%A Lutz, Beat
%A Rodríguez, Ramón
%A Codesido, Eva
%A Garcia Ladona, F. Javier
%A Bennett, Teresa A.
%A Ballesteros, Juan A.
%A Cruces, Jacobo
%A Loza, María I.
%A Benhamú Salama, Bellinda
%A Rodríguez De Fonseca, Fernando Antonio
%A López Rodríguez, María Luz
%T Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for “Diabesity”
%D 2022
%@ 0022-2623
%U https://hdl.handle.net/20.500.14352/71661
%X 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.
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