Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R).

The therapeutic success of peptidic GLP-1 receptor agonists for treatment of type 2 diabetes mellitus (T2DM) motivated our search for orally bioavailable small molecules that can activate the GLP-1 receptor (GLP-1R) as a well-validated target for T2DM. Here, the discovery and characterization of a potent and selective positive allosteric modulator (PAM) for GLP-1R based on a 3,4,5,6-tetrahydro-1-1,5-epiminoazocino[4,5-]indole scaffold is reported. Optimization of this series from HTS was supported by a GLP-1R ligand binding model. Biological in vitro testing revealed favorable ADME and pharmacological profiles for the best compound . Characterization by in vivo pharmacokinetic and pharmacological studies demonstrated that activates GLP-1R as positive allosteric modulator (PAM) in the presence of the much less active endogenous degradation product GLP1(9-36)NH of the potent endogenous ligand GLP-1(7-36)NH. While these data suggest the potential of small molecule GLP-1R PAMs for T2DM treatment, further optimization is still required towards a clinical candidate.