Structure–Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators

Abstract

Free fatty acid receptor 3 (FFA3, previously GPR41) is activated by short-chain fatty acids, mediates health effects of the gut microbiota, and is a therapeutic target for metabolic and inflammatory diseases. The shortage of well-characterized tool compounds has however impeded progress. Herein, we report structure–activity relationship of an allosteric modulator series and characterization of physicochemical and pharmacokinetic properties of selected compounds, including previous and new tools. Two representatives, 57 (TUG-1907) and 63 (TUG-2015), showed improved solubility and preserved potency. Of these, 57, with EC50 = 145 nM and a solubility of 33 μM, showed high clearance in vivo but is a preferred tool in vitro. In contrast, 63, with EC50 = 162 nM and a solubility of 9 μM, showed lower clearance and seems better suited for in vivo studies. Using 57, we demonstrate for the first time that FFA3 activation leads to calcium mobilization in murine dorsal root ganglia.

The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A

“…Therefore, the ability of compounds 1-1, 1-2, 1-3, and 1-4 to decrease forskolin-stimulated cAMP levels was tested in the presence or absence of 5 µM propionate. The potency of compound 1-2 in the absence or presence of propionate wa the same (EC50 = 0.61 ± 0.09 µM and EC50 = 0.58 ± 0.03 µM, respectively), which was in a good agreement with the potency reported by Ulven et al [22] for compound 1 (EC50 = 0.52 µM and EC50 = 0.54 µM, respectively). The potency of compound 1-1 (EC50 = 1.79 ± 0.3 µM) was slightly increased in the presence of propionate (EC50 = 0.64 ± 0.2 µM), with values close to those reported for compound 4 [23].…”

“…For a long time, the data regarding HHQ derivatives as FFA3/GPR41 agonists and antagonists has been very limited [20,21]. Recently, a new paper has been published about structure-activity relationship studies of tetrahydroquinolones as FFA3 modulators, mainly focused on 4-alkyl-and 4-heteryl-HHQ 3-carboxamides [22]. Compound 1-3 (Table 1) has been synthesized by Arena Pharmaceuticals, evaluated as a selective agonist of the FFA3/GPR41 receptor [21,22], and proposed as a potential therapeutic agent for hepatocellular carcinoma.…”

“…Recently, a new paper has been published about structure-activity relationship studies of tetrahydroquinolones as FFA3 modulators, mainly focused on 4-alkyl-and 4-heteryl-HHQ 3-carboxamides [22]. Compound 1-3 (Table 1) has been synthesized by Arena Pharmaceuticals, evaluated as a selective agonist of the FFA3/GPR41 receptor [21,22], and proposed as a potential therapeutic agent for hepatocellular carcinoma. In order to compare our compounds to literature data, we re-synthesized three previously reported compounds (1-1, 1-2, 1-3) according to published procedures [21,22], motivated by the reported experimental data regarding their activity against one receptor (FFA3/GPR41).…”

“…Compound 1-3 (Table 1) has been synthesized by Arena Pharmaceuticals, evaluated as a selective agonist of the FFA3/GPR41 receptor [21,22], and proposed as a potential therapeutic agent for hepatocellular carcinoma. In order to compare our compounds to literature data, we re-synthesized three previously reported compounds (1-1, 1-2, 1-3) according to published procedures [21,22], motivated by the reported experimental data regarding their activity against one receptor (FFA3/GPR41). There are no data on these compounds regarding the FFA2/GPR43 and HCA2/GPR109A receptors.…”

“…There have been numerous attempts to approach the problem of obtaining selective and effective ligands for modulating biochemical pathways that involve metabolite GPCRs [2,[16][17][18][19][20][21][22]. According to our knowledge, there has been no comparative study of the activities of putative ligands on these three GPCRs, namely, the free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 and the hydroxycarboxylic acid receptor HCA2/GPR109A.…”