PBI-4050

Setogepram (PBI-4050) acts as an orally active agonist for GPR40 and as an antagonist or inverse agonist for GPR84[1]. Setogepram (PBI-4050) decreases renal, liver and pancreatic fibrosis[1][2]. Setogepram (PBI-4050) exerts anti-fibrotic, anti-inflammatory and anti-proliferative actions[2].

Research Areas >> Inflammation/Immunology

Signaling Pathways >> GPCR/G Protein >> GPR40

Research Areas >> Metabolic Disease

Signaling Pathways >> GPCR/G Protein >> GPR84

GPR40, GPR84[1]

Setogepram (PBI-4050; 500 µM; 24 hours) inhibits TGF-β (10 ng/mL)-activated human hepatic stellate cells (HSCs) proliferation[2]. Setogepram (PBI-4050; 250 or 500 µM; 24hours) dose-dependently arrests HSCs at the G0/G1 phase without inducing apoptosis[2]. Cell Proliferation Assay[2] Cell Line: HSCs Concentration: 250 or 500 µM Incubation Time: 24 hours Result: Inhibited TGF-β-activated HSC proliferation. TGF-β (10 ng/mL) increased HSC proliferation by 10%. Cell Cycle Analysis[2] Cell Line: HSCs Concentration: 250 µM, 500 µM Incubation Time: 24 hours Result: Inhibited cell cycle progression.

Setogepram (PBI-4050; 100 mg/kg/day; gavage from 8-20 weeks of age) markedly decreases hyperglycemia and markedly improvea glucose tolerance in type 2 diabetes eNOS-/-db/db mice[1]. Animal Model: Type 2 diabetes eNOS-/-db/db mice[1] Dosage: 100 mg/kg/day Administration: Given via daily gavage from 8-20 weeks Result: Compared with vehicle-treated mice, hyperglycemia was markedly decreased, and glucose tolerance was markedly improved.

[1]. Li Y, et al. Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control. JCI Insight. 2018 May 17;3(10). pii: 120365.

[2]. Grouix B, et al. PBI-4050 Reduces Stellate Cell Activation and Liver Fibrosis through Modulation of Intracellular ATP Levels and the Liver Kinase B1/AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway. J Pharmacol Exp Ther. 2018 Oct;367(1):71-81.