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2-Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon-like peptide 1 receptor.
- Source :
-
Chemical biology & drug design [Chem Biol Drug Des] 2022 Jun; Vol. 99 (6), pp. 857-867. Date of Electronic Publication: 2022 Apr 04. - Publication Year :
- 2022
-
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.<br /> (© 2022 John Wiley & Sons Ltd.)
Details
- Language :
- English
- ISSN :
- 1747-0285
- Volume :
- 99
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Chemical biology & drug design
- Publication Type :
- Academic Journal
- Accession number :
- 35313084
- Full Text :
- https://doi.org/10.1111/cbdd.14039