当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R).

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Méndez M,Matter H,Defossa E,Kurz M,Lebreton S,Li Z,Lohmann M,Löhn M,Mors H,Podeschwa M,Rackelmann N,Riedel J,Safar P,Thorpe DS,Schäfer M,Weitz D,Breitschopf K

doi

10.1021/acs.jmedchem.9b01071

subject

Has Abstract

pub_date

2020-03-12 00:00:00

pages

2292-2307

issue

5

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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