Discovery of an Orally Efficacious Positive Allosteric Modulator of the Glucagon-like Peptide-1 Receptor

  • J Med Chem. 2021 Mar 25;64(6):3439-3448. doi: 10.1021/acs.jmedchem.1c00029.
Francis S Willard  1 ,  David B Wainscott  1 ,  Aaron D Showalter  2 ,  Cynthia Stutsman  2 ,  Wenzhen Ma  2 ,  Guemalli R Cardona  1 ,  Richard W Zink  1 ,  Christopher M Corkins  1 ,  Qi Chen  1 ,  Nathan Yumibe  3 ,  Javier Agejas  4 ,  Graham R Cumming  4 ,  José Miguel Minguez  4 ,  Alma Jiménez  4 ,  Ana I Mateo  4 ,  Ana M Castaño  4 ,  Daniel A Briere  2 ,  Kyle W Sloop  2 ,  Ana B Bueno  4
Affiliations
  • 1. Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
  • 2. Diabetes and Complications, Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
  • 3. Investigative Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana 46285, United States.
  • 4. Discovery Chemistry Research and Technologies, Lilly, S.A., Avda. de la Industria 30, Alcobendas, Madrid 28108, Spain.
PMID: 33721487 DOI: 10.1021/acs.jmedchem.1c00029
Abstract

The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH2 to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH2. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over β-arrestin recruitment. Ex vivo experiments show that the combination of GLP-1(9-36)NH2 and LSN3318839 produces glucose-dependent Insulin secretion similar to that of GLP-1(7-36)NH2. Under nutrient-stimulated conditions that release GLP-1, LSN3318839 demonstrates robust glucose lowering in animal models alone or in treatment combination with sitagliptin. From a therapeutic perspective, the biological properties of LSN3318839 support the concept that GLP-1R potentiation is sufficient for reducing hyperglycemia.

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