RT Journal Article
T1 Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for “Diabesity”
A1 Decara, Juan M.
A1 Vázquez Villa, María Del Henar
A1 Brea, José
A1 Alonso, Mónica
A1 Srivastava, Raj Kamal
A1 Orio Ortiz, Laura
A1 Alén Fariñas, Francisco
A1 Suárez, Juan
A1 Baixeras, Elena
A1 García Cárceles, Javier
A1 Escobar Peña, Ana Andrea
A1 Lutz, Beat
A1 Rodríguez, Ramón
A1 Codesido, Eva
A1 Garcia Ladona, F. Javier
A1 Bennett, Teresa A.
A1 Ballesteros, Juan A.
A1 Cruces, Jacobo
A1 Loza, María I.
A1 Benhamú Salama, Bellinda
A1 Rodríguez De Fonseca, Fernando Antonio
A1 López Rodríguez, María Luz
AB 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.
PB ACS
SN 0022-2623
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/71661
UL https://hdl.handle.net/20.500.14352/71661
LA eng
NO CRUE-CSIC (Acuerdos Transformativos 2022)
NO Unión Europea. FP7
NO Ministerio de Ciencia e Innovación (MICINN)
NO Junta ́ de Andalucía
NO Xunta de Galicia
DS Docta Complutense
RD 7 abr 2025