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. doi: 10.1021/acs.jmedchem.1c01842.
Juan M Decara  1 ,  Henar Vázquez-Villa  2 ,  José Brea  3 ,  Mónica Alonso  1 ,  Raj Kamal Srivastava  4 ,  Laura Orio  5 ,  Francisco Alén  5 ,  Juan Suárez  1 ,  Elena Baixeras  1 ,  Javier García-Cárceles  2 ,  Andrea Escobar-Peña  2 ,  Beat Lutz  4 ,  Ramón Rodríguez  6 ,  Eva Codesido  6 ,  F Javier Garcia-Ladona  7 ,  Teresa A Bennett  8 ,  Juan A Ballesteros  8 ,  Jacobo Cruces  6 ,  María I Loza  3 ,  Bellinda Benhamú  2 ,  Fernando Rodríguez de Fonseca  1  5 ,  María L López-Rodríguez  2
Affiliations
  • 1. Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA, Hospital Regional Universitario, Málaga E-29010, Spain.
  • 2. Departamento de Química Orgánica, Universidad Complutense de Madrid, Madrid E-28040, Spain.
  • 3. Biofarma Research group, USEF Screening Platform, CIMUS, USC, Santiago de Compostela E-15782, Spain.
  • 4. Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz 55128, Germany.
  • 5. Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, Madrid E-28040, Spain.
  • 6. Galchimia, O Pino, A Coruña E-15823, Spain.
  • 7. ABAXYS Therapeutics, Rue du Berceau, 91, Villers-la-Ville 1495, Belgium.
  • 8. ViviaBiotech S.L., Parque Científico de Madrid, Madrid E-28760, Spain.
PMID: 35349261 DOI: 10.1021/acs.jmedchem.1c01842
Abstract

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.

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