Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

Abstract

ABSTRACT. The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed non-acidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these non-carboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4.

Fatty acid 16:4(n‐3) stimulates a GPR120‐induced signaling cascade in splenic macrophages to promote chemotherapy resistance.

“…These results implied that 16:4(n-3) produces chemoresistance by activating GPR120 and not GPR40. To further support this conclusion, we tested the ability of a recently described GPR120-specific agonist—TUG-1197—that has no activity at GPR40 (27) to induce chemoresistance. As anticipated, coadministration of cisplatin and conditioned medium derived from splenocytes that were incubated with TUG-1197 induced chemoresistance to an extent similar to sCM from 16:4(n-3)-exposed splenocytes (Fig.…”

Probe-Dependent Negative Allosteric Modulators of the Long-Chain Free Fatty Acid Receptor FFA4

“…5, A–D) and TUG-1506 (Fig. 5, E–H) were used to antagonize β -arrestin-2 recruitment to FFA4 induced by synthetic agonists from each of four distinct chemotypes: TUG-891 (Shimpukade et al, 2012), TUG-1197 (Azevedo et al, 2016), GSK137647A (Sparks et al, 2014), and Cpd A (Oh et al, 2014) (Fig. 1).…”

“…TUG-891 [4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]-benzenepropanoic acid] was synthesized as described previously (Shimpukade et al, 2012). Compound 34 (TUG-1197) (2-(3-(pyridin-2-yloxy)phenyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide) was synthesized as described by Azevedo et al (2016). GSK137647A [4-methoxy- N -(2,4,6-trimethylphenyl)-benzenesulfonamide] was synthesized according to Sparks et al (2014).…”

“…Since then, not least because essential and other polyunsaturated ω -3 fatty acids with health-promoting properties are among the most potent fatty acid activators of this receptor (Hirasawa et al, 2005; Christiansen et al, 2015), there has been strong interest in better understanding the biologic functions of FFA4 and in its potential as a therapeutic target (Liu et al, 2015; Li et al, 2016). Because reported effects of FFA4 activation include regulation of glucose homeostasis (Oh et al, 2014; Azevedo et al, 2016), regulation of release of incretins and satiety-regulating hormones (Hirasawa et al, 2005), modulation of insulin sensitivity (Oh et al, 2010, 2014; Azevedo et al, 2016), and potential effects on weight gain (Ichimura et al, 2012; Mo et al, 2013; Azevedo et al, 2016), a large focus of studies on FFA4 has centered on the possibility that agonists of this receptor might be useful antidiabetic agents (Cornall et al, 2014; Zhang and Leung, 2014; Moran et al, 2016). However, it is clear that the expression pattern of FFA4, which includes high levels in the lung, in macrophage populations, and in various cancer cell types (Houthuijzen, 2016; Milligan et al, 2017), indicates a broader set of roles and potential for therapeutic interventions targeting this receptor (Milligan et al, 2017).…”

“…However, it is clear that the expression pattern of FFA4, which includes high levels in the lung, in macrophage populations, and in various cancer cell types (Houthuijzen, 2016; Milligan et al, 2017), indicates a broader set of roles and potential for therapeutic interventions targeting this receptor (Milligan et al, 2017). This has resulted in screening for, and the identification of, a number of series of FFA4 agonist ligands (Milligan et al, 2015, 2017), although chemical diversity within these series has, until recently (e.g., Sparks et al, 2014; Azevedo et al, 2016), remained rather limited and based on carboxylate-containing ligands that resemble synthetic fatty acids. FFA4 has been shown to be a potential regulator of adipocyte development and differentiation (Gotoh et al, 2007), potentially via increasing expression of the adipogenic transcription factor peroxisome proliferator activator receptor γ (PPAR γ ) (Hasan et al, 2015; Song et al, 2016).…”