%0 Journal Article
%A Decara, Juan M
%A Vazquez-Villa, Henar
%A Brea, Jose
%A Alonso, Monica
%A Srivastava, Raj Kamal
%A Orio, Laura
%A Alen, Francisco
%A Suarez, Juan
%A Baixeras, Elena
%A Garcia-Carceles, Javier
%A Escobar-Peña, Andrea
%A Lutz, Beat
%A Rodriguez, Ramon
%A Codesido, Eva
%A Garcia-Ladona, F Javier
%A Bennett, Teresa A
%A Ballesteros, Juan A
%A Cruces, Jacobo
%A Loza, Maria I
%A Benhamu, Bellinda
%A Rodriguez-de-Fonseca, Fernando
%A Lopez-Rodriguez, Maria L
%T Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity".
%D 2022
%U http://hdl.handle.net/10668/22590
%X 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.
%K Eating
%K Insulin Secretion
%K Glucose
%K Administration, Oral
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