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

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)NH 2 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)NH 2 . 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)NH 2 and LSN3318839 produces glucose-dependent insulin secretion similar to that of GLP-1(7-36)NH 2 . 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.

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

“…Allosteric modulation by PAMs that bind anywhere distinct from the orthosteric site of endogenous ligands and enhance the activity of agonists in an uncompetitive way is an alternative approach to peptide therapy 19 – 22 . Previous studies showed that several PAMs of GLP-1R, such as the most characterized electrophilic chemotype compound BETP 23 , 24 and the substituted quinoxaline compound 2 (6,7-dichloro-3-methanesulfonyl-2-tert-butylamino-quinoxaline) 25 , 26 , were able to initiate or promote receptor activation 9 , 27 .…”

Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for “Diabesity”

“…Drugs that target a GLP-1R allosteric site may improve receptor specificity, thereby reducing side effects. Most of the allosteric modulators of the GLP-1R that have been described (Figure ) display suboptimal potency and/or pharmacokinetics. − Recently, a program toward optimization of LSN3160440 has succeeded in the discovery of structurally related LSN3318839 as an orally efficacious GLP-1 modulator . Herein, we report the discovery of the small molecule V-0219 (compound 9 ), a very potent PAM of the GLP-1R that doubles insulin secretion at nanomolar concentrations and shows oral activity in rodent models of food intake and glucose handling.…”

“… 20 − 25 Recently, a program toward optimization of LSN3160440 has succeeded in the discovery of structurally related LSN3318839 as an orally efficacious GLP-1 modulator. 26 Herein, we report the discovery of the small molecule V-0219 (compound 9 ), a very potent PAM of the GLP-1R that doubles insulin secretion at nanomolar concentrations and shows oral activity in rodent models of food intake and glucose handling.…”

Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases

“…Recently, small molecules’ positive allosteric modulators (PAMs) of the GLP-1 receptor have been characterized [ 64 , 65 , 66 ]. These molecules would enhance receptor signaling when the endogenous ligand is present, thereby providing an opportunity to enhance the normal GLP-1 response selectively [ 64 ] Some of these PAMS interact with the less active form of GLP-1, potentiating the activity of GLP-1(9−36) by interacting with both the peptide and the receptor [ 64 , 65 , 66 ].…”