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

Abstract

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.

DABCO-Catalyzed Michael/Alkylation Cascade Reactions Involving α-Substituted Ammonium Ylides for the Construction of Spirocyclopropyl Oxindoles: Access to the Powerful Chemical Leads against HIV-1

“…Fluorine on the phenyl ring of 7b may have potential pharmacological properties, as more than 20% of new drugs contain at least one fluorine atom . Moreover, 7c and 7d were gained through coupling two vital pharmacophores, pyrrole and indole, respectively, onto the bioactive spirocyclopropyl oxindole molecules.…”

Non‐peptide agonists and positive allosteric modulators of glucagon‐like peptide‐1 receptors: Alternative approaches for treatment of Type 2 diabetes

“…In another effort to take advantage of the increased bioavailability and longer half‐life of GLP‐1(9–36)NH 2 , a group at Sanofi‐Aventis Deutschland GmbH performed HT screening of its own compound collection using an HTRF cAMP assay in a HEK293 cell line overexpressing the human GLP‐1 receptor, which was followed by chemical optimization of the lead compounds (Méndez et al, 2020). These efforts led to the discovery of compound 14 (compound 19 ) (Figure 3, [ 14 ]) based on a 3,4,5,6‐tetrahydro‐1 H ‐1,5‐epiminoazocino[4,5‐ b ]indole scaffold.…”

“…GLP-1 is known to bind to signal-enhanced oleoylethanolamide (OEA) or 2-oleoylglycerol but not to stearoylethanolamide (SEA) (Cheng et al, 2015). To understand the mechanism of N55, competition-binding experiments were performed to examine the effect of increasing N55 concentrations on the binding of In another effort to take advantage of the increased bioavailability and longer half-life of GLP-1(9-36)NH 2 , a group at Sanofi-Aventis Deutschland GmbH performed HT screening of its own compound collection using an HTRF cAMP assay in a HEK293 cell line overexpressing the human GLP-1 receptor, which was followed by chemical optimization of the lead compounds (Méndez et al, 2020). These efforts led to the discovery of compound 14 (compound 19) (Figure 3, [14]) based on a 3,4,5,6-tetrahydro-1H-1,5-epiminoazocino[4,5-b] indole scaffold.…”

2‐Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon‐like peptide 1 receptor

“…2‐Aminothiophenes (2‐ATs) are small molecule heterocycles (Figure 1, compound 1 ), containing a 5‐membered ring core, which are synthetically accessible in good to high yield via variants of the Gewald Reaction (Méndez et al, 2020). 2‐AT derivatives have been found to exhibit a diverse array of pharmacological and biological properties.…”