2026-06-14T14:34:14Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/187962024-09-21T20:03:30Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927
Repisalud
author
Decara, Juan M
author
Vázquez-Villa, Henar
author
Brea, José
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Alonso, Mónica
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Srivastava, Raj Kamal
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Orio, Laura
author
Alén, Francisco
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Suárez, Juan
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Baixeras, Elena
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García-Cárceles, Javier
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Escobar-Peña, Andrea
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Lutz, Beat
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Rodríguez, Ramón
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Codesido, Eva
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Garcia-Ladona, F Javier
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Bennett, Teresa A
author
Ballesteros, Juan A
author
Cruces, Jacobo
author
Loza, María I
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Benhamú, Bellinda
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Rodríguez de Fonseca, Fernando
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López-Rodríguez, María L
2024-02-27T15:16:14Z
2024-02-27T15:16:14Z
2022-03-29
10.1021/acs.jmedchem.1c01842
1520-4804
Journal of medicinal chemistry
http://hdl.handle.net/10668/22590
35349261
http://hdl.handle.net/20.500.12105/18796
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.
eng
Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity".
research article