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 del Olmo, Juan Manuel
A1 Vázquez Villa, Henar
A1 Brea Floriani, José Manuel
A1 Alonso, Mónica
A1 Srivastava, Raj Kamal
A1 Orio Ortiz, Laura
A1 Alén Fariñas, Francisco
A1 Suárez Pérez, Juan
A1 Baixeras Llano, Elena
A1 García Cárceles, Javier
A1 Escobar Peña, 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 García, María Isabel
A1 Benhamú Salama, Bellinda
A1 Rodríguez de Fonseca, Fernando
A1 López Rodríguez, María L.
K1 Carbohydrates
K1 Mixtures
K1 Peptides and proteins
K1 Rodent models
K1 Solutions
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 Publications
YR 2022
FD 2022-03-29
LK https://hdl.handle.net/10347/45118
UL https://hdl.handle.net/10347/45118
LA eng
NO 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, and María L. López-Rodríguez Journal of Medicinal Chemistry 2022 65 (7), 5449-5461 DOI: 10.1021/acs.jmedchem.1c01842
NO This work was supported by Vivia Biotech S.L. and grants from European Regional Development Fund (ERDF): Proyectos de Aplicación del conocimiento y Proyectos de Excelencia Junta de Andalucia (CTS-433 and CTS-8221) and Xunta de Galicia (GRC2014/011). Additional support came from the seventh Framework Programme of European Union (HEALTH-F2-2008-223713, REPROBESITY) and MECD (INNPACTO 01/12-CL-0-12-09, SAF2016-78792-R, and PID2019-106279RB-I00)
DS Minerva
RD 28 abr 2026