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

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.