1. 2-Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon-like peptide 1 receptor.
- Author
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Redij T, McKee JA, Do P, Campbell JA, Ma J, Li Z, Miller N, Srikanlaya C, Zhang D, Hua X, and Li Z
- Subjects
- Allosteric Regulation, HEK293 Cells, Humans, Peptides pharmacology, Small Molecule Libraries pharmacology, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 metabolism, Glucagon-Like Peptide-1 Receptor agonists, Glucagon-Like Peptide-1 Receptor metabolism
- Abstract
We report the discovery of two new 2-aminothiophene based small molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes. One of the chemotypes, (S-1), has a molecular weight of 239 g/mol, the smallest molecule among all reported GLP-1R PAMs. When combined with GLP-1 peptide, S-1 increased the GLP-1R activity in a dose-dependent manner in a cell-based assay. When combined with the peptide agonist of vasoactive intestinal polypeptide receptor 1 (VIPR1), S-1 showed no specific activity on VIPR1, another class B GPCR present in the same HEK293-CREB cell line. Insulin secretion studies found S-1 combined with GLP-1 increased insulin secretion by 1.5-fold at 5 μM. In a mechanistic study, evidence is provided that the synergistic effect of S-1 with GLP-1 may be partly due to the enhanced impact on CREB based phosphorylation. Given the favorable profile of these chemotypes, the work reported herein suggests that 2-aminothiophene derivatives are a new and promising class of GLP-1R PAMs., (© 2022 John Wiley & Sons Ltd.)
- Published
- 2022
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