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 Vazquez-Villa, Henar
A1 Brea, Jose
A1 Alonso, Monica
A1 Srivastava, Raj Kamal
A1 Orio, Laura
A1 Alen, Francisco
A1 Suarez, Juan
A1 Baixeras, Elena
A1 Garcia-Carceles, Javier
A1 Escobar-Peña, Andrea
A1 Lutz, Beat
A1 Rodriguez, Ramon
A1 Codesido, Eva
A1 Garcia-Ladona, F Javier
A1 Bennett, Teresa A
A1 Ballesteros, Juan A
A1 Cruces, Jacobo
A1 Loza, Maria I
A1 Benhamu, Bellinda
A1 Rodriguez-de-Fonseca, Fernando
A1 Lopez-Rodriguez, Maria L
K1 Eating
K1 Insulin Secretion
K1 Glucose
K1 Administration, Oral
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 American Chemical Society
YR 2022
FD 2022-03-29
LK http://hdl.handle.net/10668/22590
UL http://hdl.handle.net/10668/22590
LA en
NO Decara 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):5449-5461
NO This work was supported by Vivia Biotech S.L. and grants from European Regional Development Fund (ERDF): Proyectos de Aplicacion 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-F22008-223713, REPROBESITY) and MECD (INNPACTO 01/12-CL-0-12-09, SAF2016-78792-R, and PID2019106279RB-I00).
DS RISalud
RD Apr 7, 2025