PBI is an agonist of GPR and acts as an

PBI-4050 is an agonist of GPR40 and acts as an antagonist or inverse agonist of GPR84. It cannot be excluded that other targets besides GPR40 and GPR84 could be implicated in the mechanism of action of PBI-4050 and could be explored in future studies. However, the present study, and in particular the receptor KO models, strongly supports GPR40 and GPR84 as major mediators in pathologic fibrotic pathways and as the targets of the antifibrotic effects of PBI-4050. Our data show that PBI-4050 significantly attenuated fibrosis in a variety of injury contexts, as evidenced with the antifibrotic activity observed in kidney, liver, lung, heart, pancreas, and skin fibrosis models. Given our findings with both Gpr40 and Gpr84 KO mice, both receptors appear to be involved in the fibrotic pathways. Considering their Methylprednisolone Sodium Succinate along the nephron, within the glomerulus, and in numerous bone marrow–derived cell types, it is likely that GPR40 and GPR84 modulate profibrotic, inflammatory, and epithelial-mesenchymal transition processes. Therefore, GPR40 may partially protect against development of fibrosis, whereas GPR84 may induce the promotion and stimulation of fibrosis, as observed with the significant increase in fibrosis in Gpr40−/− mice and reduction of fibrosis in Gpr84−/− mice. The dual modulator PBI-4050 reinforces the involvement of both GPR40 and GPR84 in multiple models of fibrosis. In the context of the adenine-induced CKD model, treatment of Gpr40 and Gpr84 KO mice with PBI-4050 suggests its antifibrosis effects to be mainly mediated by GPR40 activation, whereas inhibition of GPR84 mostly accounts for reduction of cystic lesions. The relative role of each receptor may vary depending on the type of insult, pathology, and organ. Future work will aim to elucidate the precise intracellular signaling pathways used by both GPR40 and GPR84 to regulate fibrotic events in the pathogenesis of disease. The inhibition of fibrotic and inflammatory markers by PBI-4050, found in human proximal tubule epithelial cells, podocytes, and primary fibroblasts (Figure 3), suggests that the attenuation of fibrosis that we have shown in various rodent fibrosis models could translate to human disease. Moreover, significant clinical activity observed in recent phase 2 clinical trials in type 2 diabetes subjects with metabolic syndrome and in idiopathic pulmonary fibrosis patients confirm translation of pharmacologic activity of PBI-4050 in humans. Of interest, PBI-4050 was well tolerated and demonstrated a good safety profile in these two early-phase clinical trials.
Introduction Type 2 diabetes mellitus (T2DM) is a metabolic disorder disease characterized by both defective insulin secretion and insulin action in maintaining glucose homeostasis [1]. T2DM often leads to multiple macrovascular and microvascular complications, including cardiovascular diseases, nephropathy, neuropathy and retinopathy [[2], [3], [4]]. The incidence of T2DM is increasing at an alarming rate. By 2017, the number of individuals affected worldwide was about 425 million and this figure may reach 629 million in 2045 [5]. This severe situation, along with the undesirable side effects caused by current hypoglycemic agents, such as high risk of hypoglycemia, body weight gain and gastric symptoms [[6], [7], [8]], stimulate urgent needs for novel drugs with improved safety and glycemic control. Free fatty acid receptor 1 (FFAR1, also known as GPR40) belongs to the family of G protein-coupled receptors (GPCRs) and was de-orphanized in 2003 as a receptor for medium-to long-chain free fatty acids (FFAs) [9,10]. Mainly expressed in beta cells of pancreatic islets, GPR40 can be activated by the endogenous FFAs, which subsequently elicit amplified glucose-dependent insulin secretion without high risk of hypoglycemia [9,[11], [12], [13], [14], [15]]. GPR40 is also expressed in the incretin-producing enteroendocrine L cells of the intestinal tract and its activation results in secretion of incretins such as glucagon like peptide 1 (GLP-1) [16,17]. Therefore, the ability of GPR40 to regulate glucose homeostasis by two mechanisms, glucose-stimulated insulin secretion and incretin secretion, makes it an excellent target for T2DM drug development [18,19].