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-1H-1,5-epiminoazocino­[4,5-b]­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 19. Characterization by in vivo pharmacokinetic and pharmacological
studies demonstrated that 19 activates GLP-1R as positive
allosteric modulator (PAM) in the presence of the much less active
endogenous degradation product GLP1(9–36)­NH2 of
the potent endogenous ligand GLP-1(7–36)­NH2. While
these data suggest the potential of small molecule GLP-1R PAMs for
T2DM treatment, further optimization is still required towards a clinical
candidate.