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    • Through the analysis of various synthetic GPR agonists as re

    2021-12-01

    Through the analysis of various synthetic GPR40 agonists as reported in literature, we found that a number of these compounds contained a phenylpropanoic 4-aminopyridine motif which was inspired from naturally occurring medium to long chain fatty acids. For instance, in the early period of discovering TAK-875, it was found that lead compound 1 exhibited potent GPR40 agonist activity and a significant insulinotropic effect in diabetic animal models. However, low sustainability of this compound in rat, likely due to its susceptibility to β-oxidation at the 3-phenylpropanoic acid moiety discouraged further advancement of this compound down the drug discovery pipeline [8]. Hence, for improving the metabolic stability of GPR40 agonists bearing 3-phenylpropanoic acid moiety, successful design strategies such as introducing small residues in the β-position to the acid group or cyclizing the β-position to the benzene ring were applied to block the active site of metabolism. In the course of this work, we initially employed a scaffold hopping strategy, replacing the propionic acid moiety in compound 1 with different functional groups such as a propiolic acid fragment. We hypothesized that this strategy would eliminate issues related to β-oxidaion of 3-phenylproponic acid moiety, leading to investigation of novel GPR40 agonists with improved metabolic stability.
    Results and discussion GPR40 receptor is generally considered to be a Gq-coupled receptor [[10], [11], [12]]. After Gq-coupled GPCR activation, the membrane lipid phosphatidylinositol 4, 5-bisphosphate to generate inositol triphosphate (IP3) and diacylglycerol (DAG), IP3 can activate IP3 receptor (IP3R) and release Ca2+ from the endoplasmic reticulum (ER) [13]. The agonistic activity of these synthetic compounds was investigated by a calcium flux assay using HEK293-GPR40 cells. Two known GPR40 agonists, TAK-875 and linolenic acid, were served as positive controls [14]. Maximal efficacy (Emax) was determined as percent response relative to that of 30 μM linolenic acid. All of the tested compounds were initially tested at a concentration of 10 μM and those demonstrated more than 50% agonist response shown by linolenic acid were further evaluated for their EC50 values. We firstly evaluated the agonistic activity of compounds 4, 6a, 6b, 8a, 8b, and 9, which were designed to avoid potential β-oxidation. None of these compounds displayed more than 50% Emax as compared to linolenic acid, with the exception of compound 9 which demonstrated 90% Emax and an EC50 value of 0.4 μM. As shown in Fig. 1, introducing one more methyl group or removing both methyl groups in the terminal phenyl ring of compound 9 led to a decrease in potency (10, EC50 = 2.87 μM; 12, EC50 = 3.77 μM), while compound 11 having only one methyl group retained the agonist activity (11, EC50: 0.61 μM). Replacement of the methyl group in compound 11 with a trifluoromethoxy or isopropyl group yielded 13 and 15 which were less potent than parent compound (13, EC50: 2.85 μM; 15, EC50: 3.98 μM), however compound 14 with a chlorine substitution maintained the activity indicating that a substituent having a similar size to a methyl group was preferred. With the exception of compound 18 showing moderate agonist activity (EC50 = 1.80 μM), compounds bearing substitution at the meta-position or para-position in the terminal phenyl ring generally lost their activities. Similarly, 2,4- or 2,5-substitution analogs 23 and 24 were found to exhibit poor agonist activity. In addition, two diphenyl ether analogs prepared only displayed modest to weak activity (25, EC50: 1.10 μM; 26, EC50: 4.02 μM), and introducing a methylene group to the terminal phenyl ring of compound 25 completely lost its activity (27, EC50 > 10 μM). Collectively, we have identified a series of novel GPR40 agonists bearing phenylpropiolic acid scaffold and the best three compounds in this series 9, 11, and 14 exhibited submicromolar agonistic activity and similar agonist response (Emax) to that of positive control TAK-875 (Fig. 2A). Moreover, when incubated with rat liver microsomes, at least 80% of compounds 9, 11, and 14 remained unchanged after 1 h incubation at 10 μM (data not shown), suggesting that these compounds were likely devoid of β-oxidation occurred in compound 1.