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

Willard, Francis
S.; Wainscott, David B.; Showalter, Aaron D.; Stutsman, Cynthia; Ma, Wenzhen; Cardona, Guemalli R.; Zink, Richard W.; Corkins, Christopher M.; Chen, Qi; Yumibe, Nathan; Agejas, Javier; Cumming, Graham R.; Minguez, José Miguel; Jiménez, Alma; Mateo, Ana I.; Castaño, Ana M.; Briere, Daniel A.; Sloop, Kyle W.; Bueno, Ana B.

doi:10.1021/acs.jmedchem.1c00029.s001

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

journal contribution

posted on 2021-03-15, 22:43 authored by Francis S. Willard, David B. Wainscott, Aaron D. Showalter, Cynthia Stutsman, Wenzhen Ma, Guemalli R. Cardona, Richard W. Zink, Christopher M. Corkins, Qi Chen, Nathan Yumibe, Javier Agejas, Graham R. Cumming, José Miguel Minguez, Alma Jiménez, Ana I. Mateo, Ana M. Castaño, Daniel A. Briere, Kyle W. Sloop, Ana B. Bueno

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.