Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R)
| Autor: | Elisabeth Defossa, Matthias Löhn, Matthias Schäfer, Pavel Safar, Dietmar Weitz, Kristin Breitschopf, Matthias Lohmann, María Méndez, David S Thorpe, Jens Riedel, Nils Rackelmann, Hartmut Mors, Hans Matter, Michael Kurz, Ziyu Li, Michael Podeschwa, Sylvain Lebreton |
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| Rok vydání: | 2019 |
| Předmět: |
Blood Glucose
Male endocrine system Allosteric modulator Allosteric regulation Pharmacology 01 natural sciences Glucagon-Like Peptide-1 Receptor Rats Sprague-Dawley Mice 03 medical and health sciences Allosteric Regulation In vivo Drug Discovery Animals Humans Hypoglycemic Agents Receptor Cells Cultured 030304 developmental biology ADME 0303 health sciences Chemistry HEK 293 cells Small molecule In vitro Rats 0104 chemical sciences Mice Inbred C57BL Molecular Docking Simulation 010404 medicinal & biomolecular chemistry HEK293 Cells Diabetes Mellitus Type 2 Drug Design Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 63:2292-2307 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01071 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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