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    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.


    Juan 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, María L López-Rodríguez. Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity". Journal of medicinal chemistry. 2022 Apr 14;65(7):5449-5461

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    PMID: 35349261

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