Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity".

Decara, Juan MVazquez-Villa, HenarBrea, JoseAlonso, MonicaSrivastava, Raj KamalOrio, LauraAlen, FranciscoSuarez, JuanBaixeras, ElenaGarcia-Carceles, JavierEscobar-Peña, AndreaLutz, BeatRodriguez, RamonCodesido, EvaGarcia-Ladona, F JavierBennett, Teresa ABallesteros, Juan ACruces, JacoboLoza, Maria IBenhamu, BellindaRodriguez-de-Fonseca, FernandoLopez-Rodriguez, Maria L2023-05-032023-05-032022-03-29Decara JM, Vázquez-Villa H, Brea J, Alonso M, Srivastava RK, Orio L, et al. Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity". J Med Chem. 2022 Apr 14;65(7):5449-5461http://hdl.handle.net/10668/22590Peptidic 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/EatingInsulin SecretionGlucoseAdministration, OralAnimalsDiabetes Mellitus, Type 2Glucagon-Like Peptide-1 ReceptorObesityPeptidesDiscovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity".research article35349261open accessObesidadIngestión de AlimentosReceptor del Péptido 1 Similar al GlucagónSecreción de InsulinaGlucosaAdministración Oral10.1021/acs.jmedchem.1c018421520-4804PMC9014410https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c01842https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014410/pdf