Selective novel inverse agonists for human GPR43 augment GLP-1 secretion

Area of Science:

• Pharmacology
• Molecular Biology
• Metabolic Diseases

Background:

• GPR43 (FFAR2) is activated by short-chain fatty acids and linked to inflammation, obesity, and type 2 diabetes, but its in vivo functions remain debated.
• Contradictory data exist regarding GPR43's physiological roles, necessitating further investigation into its signaling pathways and therapeutic targeting.
• Understanding GPR43 modulation is crucial for developing treatments for metabolic and inflammatory conditions.

Purpose of the Study:

• To identify and characterize novel selective inverse agonists of human GPR43 (FFAR2).
• To investigate the effects of these compounds on GPR43 downstream signaling pathways.
• To explore the potential of these modulators in augmenting GLP-1 secretion.

Main Methods:

• Synthesis and screening of pyrimidinecarboxamide derivatives to identify GPR43 inverse agonists.
• Structure-activity relationship (SAR) studies to optimize compound potency and selectivity.
• Analysis of cyclic AMP levels, cytoplasmic Ca(2+) levels, and downstream signaling pathways (ERK, p38 MAPK, NF-κB).
• Assessment of glucagon-like peptide 1 (GLP-1) secretion in NCI-H716 cells.

Main Results:

• BTI-A-404 identified as a selective inverse agonist of human GPR43, with BTI-A-292 also showing activity.
• Compounds increased cyclic AMP levels and decreased acetate-induced cytoplasmic Ca(2+) levels.
• Modulation of ERK, p38 MAPK, and NF-κB signaling pathways was observed.
• Significant augmentation of GLP-1 secretion in NCI-H716 cells by both compounds.

Conclusions:

• Novel pyrimidinecarboxamide compounds BTI-A-404 and BTI-A-292 are potent and selective inverse agonists of human GPR43.
• These compounds effectively modulate key GPR43 signaling pathways.
• The observed enhancement of GLP-1 secretion highlights their therapeutic potential for metabolic disorders.