Synthesis and evaluation of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives as FFA4 agonists

Article abstract of DOI:10.1016/j.bmcl.2020.127650

Free fatty acid receptor 4 (FFA4) has been recognized as an attractive target in metabolic diseases. To find potent and selective FFA4 agonist, 28 compounds of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives were designed and synthesized, featuring O[sbnd]C and SO2-N linkage. For the O[sbnd]C linkage compounds, 1g showed the most potent FFA4 agonistic activity with a pEC₅₀ of 5.81 ± 0.04 and exhibited at least 64-fold selectivity against FFA1. For SO2-N linkage agonists, 2m had a pEC₅₀ of 5.66 ± 0.04 and displayed>46-fold selectivity against FFA1. Among these two series of compounds, 1g was the most potent agonist at FFA4 and the best selectivity against FFA1, demonstrated by docking simulation. Moreover, 1g showed receptor selectivity on other seven GPCRs. In anti-diabetic evaluation, 1g dose-dependently reduced blood glucose, which was better than a clinical phase III drug TAK875. This study provides guidance for FFA4 ligand design and drug optimization.

Full text of DOI:10.1016/j.bmcl.2020.127650

Journal Pre-proofs
Synthesis and Evaluation of 3-(4-(phenoxymethyl)phenyl)propanoic Acid and
N-phenylbenzenesulfonamide Derivatives as FFA4 Agonists
Fangfang Xu, Yaopeng Zhao, Han Zhou, Chunzhi Li, Xiuli Zhang, Tao Hou,
Lala Qu, Lai Wei, Jixia Wang, Yanfang Liu, Xinmiao Liang
PII:
S0960-894X(20)30761-7
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127650
BMCL 127650
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Bioorganic & Medicinal Chemistry Letters
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Accepted Date:
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20 October 2020
23 October 2020
Please cite this article as: Xu, F., Zhao, Y., Zhou, H., Li, C., Zhang, X., Hou, T., Qu, L., Wei, L., Wang, J., Liu,
Y., Liang, X., Synthesis and Evaluation of 3-(4-(phenoxymethyl)phenyl)propanoic Acid and N-
phenylbenzenesulfonamide Derivatives as FFA4 Agonists, Bioorganic & Medicinal Chemistry Letters (2020),
doi: https://doi.org/10.1016/j.bmcl.2020.127650
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Synthesis and Evaluation of 3-(4-
(phenoxymethyl)phenyl)propanoic Acid and N-
phenylbenzenesulfonamide Derivatives as FFA4
Agonists
Fangfang Xua,b,e, Yaopeng Zhaoa,e, Han Zhoua, Chunzhi Lic, Xiuli Zhangd, Tao Houa, Lala Qua,
Lai Weia, Jixia Wanga,*, Yanfang Liua,*, Xinmiao Lianga,*
aKey Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, Dalian 116023, China
bUniversity of Chinese Academy of Sciences, Beijing, 100049, China
cState Key Laboratory of Catalysis, iChEM, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China
d College of Pharmaceutical Sciences, Soochow University, Suzhou, 215006, China
e These authors contributed equally.
*Corresponding Authors at: Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, China.
1

E-mail addresses: jxwang@dicp.ac.cn (J. Wang), liuyanfang@dicp.ac.cn (Y. Liu),
liangxm@dicp.ac.cn (X. Liang)
Phone: +86 411 84379519
ABSTRACT
Free fatty acid receptor 4 (FFA4) has been recognized as an attractive target in metabolic
diseases. To find potent and selective FFA4 agonist, 28 compounds of 3-(4-
(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives were
designed and synthesized, featuring O-C and SO2-N linkage. For the O-C linkage compounds,
1g showed the most potent FFA4 agonistic activity with a pEC50 of 5.81 ± 0.04 and exhibited at
least 64-fold selectivity against FFA1. For SO2-N linkage agonists, 2m had a pEC50 of 5.66 ±
0.04 and displayed more than 46-fold selectivity against FFA1. Among these two series of
compounds, 1g was the most potent agonist at FFA4 and the best selectivity against FFA1,
demonstrated by docking simulation. Moreover, 1g showed receptor selectivity on other seven
GPCRs. In anti-diabetic evaluation, 1g dose-dependently reduced blood glucose, which was
better than a clinical phase Ⅲ drug TAK875. This study provides guidance for FFA4 ligand
design and drug optimization.
Keywords: Free fatty acid receptor 4; GPR120; Agonist; Dynamic mass redistribution; Type 2
diabetes
Free fatty acid receptor 4 (FFA4, also known as GPR120) has been recognized as an attractive
target for treatment of metabolic diseases, such as type 2 diabetes and obesity [1]. The receptor is
activated by long chain fatty acids. Functionally, it is a member of lipid binding G-protein
2

coupled receptors (GPCRs) that include GPR40 (also known as FFA1), GPR41, GPR43 and
GPR120 [2]. FFA4 agonist has been proved to improve insulin resistance in obese mice [3].
Besides, a report has found that a non-synonymous mutation of human FFA4 increased the risk
of being obese in European people [4]. Moreover, it has been found that the ω-3 fatty acids
activated ciliary FFA4 to regulate adipogenesis [5]. These results support a significant role of
FFA4 receptor in metabolic diseases. Therefore, identification of selective FFA4 agonists is of
great importance for investigating the biological functions of FFA4, and opening new
opportunities for related disease treatment.
Since the endogenous ligands of FFA4 and FFA1 highly overlap, identification of agonists
with high selectivity for FFA4 is a challenge for researchers. In 2008, Suzuki et al. developed the
first carboxylic acid-containing FFA4-selective agonist 12 through modifying PPARγ agonists
[6]. In 2012, TUG891 with phenylpropionic acid scaffold was disclosed as a potent and selective
FFA4 agonist [7]. However, TUG891 exhibits limited selectivity for murine FFA4 against
murine FFA1, limiting its use in studying specific pharmacologic functions on murine-derived
cell lines that co-express both receptors [8]. Subsequently, a number of carboxylic acid-
containing agonists were reported [9-11]. This indicated that carboxylic acid is important for the
agonistic activity of FFA4. In 2010, a series of nonacidic benzosultams derivatives were
identified as FFA4 agonists structurally different from other known FFA4 agonists [12].
Recently, Sparks et al. reported a series of nonacidic sulfonamide FFA4 agonists, like
GSK137647A, with pEC50 value 6.3 and lack of activity on FFA1 [13]. Although a number of
FFA4 agonists have been identified, there are a relatively few agonists with high activity
available, and structural diversity is still scarce. Further research is still needed to develop potent,
selective, and bioavailable FFA4 agonists.
3

Inspired by structures of known FFA4 agonists, they shared some commonalities, basically
having two aromatic rings linked by C-O, C-N or SO2-N (Fig. 1) [7, 13-17]. The position of O in
C-O linkage was located close to the benzene ring containing the -COOH group. The effect of
the position change of C-O linkage to O-C linkage on agonistic activity at FFA4 is not reported.
In this study, through a structure-activity relationship (SAR) study, a potent and selective O-C
linkage FFA4 agonist (1g) with anti-diabetic activity was identified. Given that carboxylic acids
(usually linked by C-O, C-N) and sulfonamides (usually linked by SO2-N) are mainly two
categories FFA4 agonists, we also study a series of compounds with SO2-N linkage, and a potent
SO2-N linked FFA4 agonist (2m) with excellent selectivity against FFA1 was developed.
Fig. 1. Representative FFA4 agonist [6, 7, 13-17].
A series of O-C linkage compounds were synthesized. The general synthetic routes to prepare
these compounds 1a to 1g are outlined in Scheme 1.
4

Scheme 1. General synthesis of the O-C linkage derivatives. Reagents and conditions: (a) K2CO3, RT,
84~95%; (b) NiCl26H2O, NaBH4, 0 ℃, 24.5-98%; (c) NaOH or LiOH, RT, 27-93%; (d) Pd(PPh3)4, K2CO3, 75
℃, 71%.
The general synthesis of the SO2-N linkage agonists is shown in Scheme 2. The synthesis is
very simple through one step reaction. Sulfonamide bond was formed by reaction of the phenyl
sulfonamide and aryl bromides except compound 2g. The synthetic routes to prepare compound
2g are outlined in Scheme 3.
Scheme 2. General synthesis of the SO2-N linkage agonists. Reagents and conditions: K2CO3, CuI, DMEDA,
70 ℃.
Scheme 3. Synthesis of the 2g. Reagents and conditions: THF, RT, TEA, overnight.
Dynamic mass redistribution (DMR) assays afforded by label-free resonant waveguide grating
(RWG) biosensors were used to profile compound activity at the CHO-K1-hFFA4 cell line.
TUG891 was used as a positive control probe [18]. All compounds stimulated a dose-dependent
5

DMR in CHO-K1-hFFA4 cells, implying that these compounds acted as FFA4 agonists (Table
1). For the selective evaluation over FFA1 receptor, these compounds were tested for activation
signals in CHO-K1-hFFA1 cells using DMR assays. Their potency on FFA1 and selectivity
between FFA4 and FFA1 were shown in Table 1.
Table 1 Potency of compounds in human FFA4 and FFA1 using DMR assays
Human FFA4
Human FFA1
pEC50
compound
R1
R2
R1’
R2’
R3’
Selectivity
pEC50 (efficacy)
1a
1b
1c
1d
1e
1f
CH2CH2COOH
CH2CH2COOH
CH2CH2COOH
CH2CH2COOH
CH2CH2COOH
CH2CH2COOH
CH2CH2COOH
NH2
H
H
CH3
H
H
F
F
5.28 ± 0.04 (84)
5.02 ± 0.02 (80)
5.24 ± 0.04 (82)
5.22 ± 0.04 (86)
> 4
4.72 ± 0.03
4.51 ± 0.17
4.52 ± 0.04
4.69 ± 0.05
> 4
4
4
OCH3
H
Br
H
F
5
H
CN
H
F
3
H
COOH
H
F
-
H
COOCH3
H
F
5.01 ± 0.04 (54)
5.81 ± 0.04 (78)
> 4
> 4
>10
>64
-
1g
2a
2b
2c
2d
2e
2f
H
4-methylphenyl
H
F
> 4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
> 4
NH2
NO2
CH3
F
H
4.75 ± 0.07 (24)
> 4
> 4
>5
-
NH2
H
> 4
NH2
H
4.20 ± 0.08 (58)
5.06 ± 0.06 (87)
~ 4.30 (68)
> 4
>1
>11
>2
-
NH2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
> 4
NH2
OH
ph
NO2
F
> 4
2g
2h
2i
NH2
> 4
> 4
NH2
4.89 ± 0.06 (54)
5.05 ± 0.03 (55)
5.31 ± 0.02 (95)
5.29 ± 0.03 (95)
~ 4.51 (99)
> 4
>8
>11
~11
~6
>3
>46
NH2
> 4
2j
NH2
Cl
Br
OCF3
CH3
~ 4.25
4.54 ± 0.06
> 4
2k
2l
NH2
NH2
2m
NH2
5.66 ± 0.04 (104)
> 4
6

2n
2o
NH2
NH2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
H
CH2CH3
H
H
5.40 ± 0.14 (109)
5.45 ± 0.05 (95)
~ 4.40 (84)
> 4
>24
>28
~2
3
H
OCH3
> 4
2p
NH2
H
C(CH3)3
H
4.17 ± 0.05
4.27 ± 0.17
4.54 ± 0.08
> 4
2q
NH2
NO2
H
H
H
4.66 ± 0.04 (73)
4.64 ± 0.06 (67)
4.66 ± 0.08 (56)
5.34 ± 0.03 (85)
4.53 ± 0.09 (104)
6.80 ± 0.03 (100)
2r
NH2
CH3
H
1
2s
NH2
F
F
H
>5
2
2t
NH2
H
H
Br
CH3
H
CH3
H
4.97 ± 0.08
4.31 ± 0.05
4.47 ± 0.09
2u
H
2
TUG891
CH2CH2COOH
4-methylphenyl
F
217
Compound 1a ~ 1g are O-C (X-Y) linkage compounds and 2a ~ 2u are SO2-NH (X-Y) linkage compounds.
Selectivity equals EC50 (FFA1)/EC50 (FFA4).
These compounds could be divided into two categories according to the X-Y linker. SAR
study of the O-C linker compounds found that common small substitutions at the R1’ position
were unfavorable for agonistic activity as indicated by the pEC50 of 1a ~ 1d in Table 1.
Therefore, strong hydrophilic and large lipophilic groups were tried such as COOH and 4-
methylphenyl. Results showed that 1e was little active (pEC50 > 4), while 1g had the highest
potency (pEC50 = 5.81 ± 0.04), and 1f had a relatively low potency (pEC50 = 5.01 ± 0.04) (Fig.
2a), which revealed that a COOH (strong hydrophilic group) at R1’ position was detrimental to
the potency of compound and large lipophilic groups were beneficial. Compared with small
lipophilic groups of -CH3 (1a) or -OCH3 (1b) at R1’ position, large lipophilic groups, such as 4-
methylphenyl (1g) was more effective. Replacement O-C linker with SO2-N developed a series
of non-acidic agonists. Substitution in the R2 position of the “right hand” benzene ring with a -
CF3 (2e) provided 7-fold and more than 22-fold increase in FFA4 potency compared with -F (2d)
and -CH3 (2c) group, respectively (Fig. 2b). When R2 position was substituted with electron-
donating group, the compounds were substantially free of FFA4 activity as indicated by
compound 2c (Table 1). It highlighted the importance of the electron-withdrawing group in the
R2 position. Next we maintained the -CF3 in the R2 position, and studied the SAR of the “left
7

hand” benzene ring in the R2’ position. Changing the R2’ position from -CH3 (2m) to -OCF3 (2l)
resulted in approximately an order of magnitude loss in FFA4 potency (Fig. 2c). Changing of the
R2’ position from a -CH3 to halogen (2i, 2j and 2k) resulted in a moderate loss of FFA4 potency.
It suggested that the electron donating group in the R2’ position was advantageous for the
agonistic activity. However, substitution with -OH in the R2’ demonstrated worse potency (2f),
which may indicate that strong hydrophilic groups are unfavorable. Further studies showed that
the large volume groups at the R2’ were not conducive to the activity. As the benzene ring in the
para-substitution completely abolished FFA4 activity (2g) and tertiary butyl substitution (2p)
decreased FFA4 potency compared with -CH2CH3 group (2n) (Fig. 2d).
Then we continued to maintain CF3 at R2 position of SO2-N linker compounds, but
replacement of R2’ with H, and studied the SAR at R1’ position. Results showed that substitution
at R1’ position (ortho-substitution) was not tolerated in contrast to para-substitution (R2’
position), since it resulted in approximately an order of magnitude loss in FFA4 potency of 2r
compared with 2m. Therefore, we have tried to construct ortho-para and meta-para disubstituted
compounds. The results showed that the potency of FFA4 did not improve as indicated by the
pEC50 of 2s and 2t. This indicated that the double substitution on the “left hand” benzene ring
was not significant for the improvement of activity. At the same time, we examined the effect of
NH2 at the R1 position. The results showed that when NH2 at R1 position was replaced by H, it
was unfavorable for activity because the EC50 of 2u is an order of magnitude larger than that of
2m. In general, the SAR around the left benzene ring was not satisfactory and did not yield the
active compound at the nanomolar level. But most of compounds showed pretty good selectivity
to FFA4 against FFA1 (Table 1). Structure-activity results indicated that lipophilic electron
donating groups at R2’ position such as -CH3 and -OCH3 favored the selectivity to FFA4.
8

However, substitutions at the R1’ or R3’ were detrimental to the selectivity of SO2-N linker
compounds. Among them, 2m displayed the best FFA4 activity (pEC50 of 5.66 ± 0.04) and
selectivity (> 46 more potent on FFA4 than FFA1).
Fig. 2. Structure-activity relationship analysis of compounds. (a) The amplitudes of the DMR induced by
compounds 1e, 1f, and 1g. (b) The amplitudes of the DMR induced by compounds 2e, 2d and 2c. (c) The
amplitudes of the DMR induced by compounds 2m, 2l and 2e. (d) The amplitudes of the DMR induced by
compounds 2n, 2g and 2p. The data represents mean ± s.d. from two independent assays, each with three
replicates (n = 6).
Observing the three-dimensional (3D) structures of 1a, 1b, 1g and the endogenous ligand α-
linolenic acid (ALA) (Fig. S1, Supplementary data), it was found that when the R1’ position
was a large lipophilic group (1g), the 3D structure formed was the most similar to the 3D
structure of ALA, which is like to the letter "L". It may be more beneficial for binding to the
9

FFA4 receptor. At the same time, we also found that the large lipophilic group at R1’ position
was beneficial to improve the selectivity over FFA1 as 1g showed 64-fold more potent on FFA4
(Table 1). To further examine the agonistic activities of these O-C linker compounds, we
conducted docking simulation in a FFA4 homology model. The homology model was built by
multiple sequence alignment including five sequences. Firstly, a docking simulation of O-C
linker compounds (except compound 1e with pEC50 > 4), together with ALA, an endogenous
ligand for FFA4, was performed using AutoDock Vina [19]. We calculated the affinity energy
between the compounds and the FFA4 model. A plot of relative DMR EC50 activity versus
calculated affinity energy (Fig. 3) showed a high correlation between the calculated affinity
energy and DMR activities (R = 0.9289). The results showed that a docking simulation using the
constructed FFA4 homology model could be useful in predicting the agonistic activity of O-C
linker compounds.
Fig. 3. Structure-activity relationships of FFA4 ligands. The relative DMR activity (x-axis) versus the
calculated affinity energy of interaction based on modeling (y-axis) was plotted.
10

An inspection of the stimulated FFA4/ALA complex showed that there were two hydrogen
bonds and one salt bridge between the carboxylate of ALA and the guanidine of Arg 24 (Fig.
4a). For FFA4/1g complex (Fig. 4b), there were one hydrogen bond and one salt bridge between
the carboxylate of compound 1g and the guanidine of Arg 24. Moreover, there were one π-cation
interaction between the benzene ring of compound 1g and guanidine of Arg 22. However, for
complex FFA4/1a and FFA4/1b, results showed that there were two hydrogen bonds and one salt
bridge between the carboxylate of both compounds and guanidine of Arg 22 (Fig. 4c and Fig.
4d). Additionally, a π-π interaction formed between the benzene ring of both compounds and
benzene ring of Phe216. The calculation results in this study suggested that the substituent on the
R1’ with large lipophilic group (compound 1g) might alter the conformation of the compound in
the ligand binding domain, which affected the interaction between its carboxylate and the
guanidine of Arg 24 or Arg 22. The large lipophilic group on the R1’ position may bring the
carboxylate closer to Arg 24 and make the interaction stronger with the guanidine of Arg 24 via
salt bridge and hydrogen bond, which might induce a more potent activation of FFA4. Therefore,
SAR study, 3D structure analysis and docking simulation suggested that 1g was the most potent
ligand with agonistic activity among O-C linker compounds. We were gratified to find that both
types of modifications led to analogues with FFA4 potency. In particular, 1g exhibited the best
agonistic activity among these compounds (pEC50 of 5.81 ± 0.04). Moreover, it had superior
selectivity for FFA4 over FFA1 (Fig. S2, Supplementary data).
11

Fig. 4. FFA4 homology model (PDB code: 1u19, 4zj8, 3odu, 4lde and 5gli) docked with (a) ALA (b) 1g (c) 1a
and (d) 1b. The yellow dashed lines indicate hydrogen bonds between the compounds and the Arg 22 or Arg
24. The pink dashed lines indicate salt bridge between the compounds and Arg 22 or Arg 24. The blue dashed
lines indicate π-π between the compounds and Phe 216. The green dashed lines indicate π-cation between the
compounds and Arg 22.
Receptor selectivity was conducted among seven different targets including muscarinic
receptor (M1), opioid receptor (µOPR), histamine receptor (H2), adrenergic receptor (β2),
endothelin receptor (ETA and ETB) and orphan receptor (GPR35) by DMR desensitization
assays using corresponding probes. The results showed that 1g was almost unable to reduce the
response of the corresponding probe at these seven receptors (Fig. 5), which suggested that 1g
was selective for FFA4, showing at least 20-fold selectivity against the seven GPCRs (estimating
12

at 50% desensitization concentration of 1g at these 7 receptors). Consequently, it was selected
for further in vivo evaluation.
Fig. 5. 1g to desensitize the probes of corresponding receptors. For M1, µOPR, ETA, ETB and H2, the
concentration of 1g was at 20 µM. For GPR35 and β2, the concentration of 1g was at 40 µM.
Given the promising in vitro profiles, 1g was assessed the in vivo anti-diabetic properties using
oral glucose tolerance test (OGTT) in db/db mice. The db/db mice were intraperitoneally
administered compound solution once before being dosed with glucose (1 g/kg body weight, po).
It showed a dose response for lowering plasma glucose in OGTT (Fig. 6). Compound 1g at 10
mg/kg and 20 mg/kg dose-dependently reduced plasma glucose levels with AUC (area under the
curve) values of 43.7% and 68.8%, respectively. As a positive control, TAK875, this had entered
clinical phase Ⅲ, reduced plasma glucose levels with an AUC value of 21.4% at 10 mg/kg in the
same study. This indicates that 1g has a stronger glucose lowering effect than TAK875 at the
same dose. 1g displayed the most pronounced effect on blood glucose lowering in 1 h post
stimulation.
13

As a whole, 1g exhibited anti-diabetic activity in oral glucose tolerance test. These results
provide guidance for drug design for the treatment of FFA4 related disorders.
Fig. 6. Glucose lowering effects as measured by OGTT. Time-dependent changes of plasma glucose levels. (n
= 3 mice per group; **p ≤ 0.01, ***p ≤ 0.001, two-way ANOVA with Bonferroni posttests). The db/db mice
were intraperitoneally administered compound solution once before being dosed with glucose (1 g/kg body
weight, po).
In the study, the optimization of a series twenty-eight of O-C and SO2-N linkage FFA4
agonists and their SAR were investigated. Selected compound from the O-C linkage series
displayed the most potent FFA4 agonistic activity with a pEC50 of 5.81 ± 0.04, possessed at least
64-fold selectivity against FFA1, and also displayed significant anti-diabetic activity in db/db
mice. Docking simulation was applied to study the interaction of O-C linkage compound, and it
might be useful in predicting the agonistic activity. Besides, most SO2-N linkage agonists
displayed good selectivity to FFA4 against FFA1. 2m showed the most potent FFA4 activity
with a pEC50 of 5.66 ± 0.04, exhibited more than 46-fold selectivity against FFA1. The results
may offer new future directions for researchers pursuing FFA4 agonists.
Acknowledgments
14

This work was supported by National Science and Technology Major Project (2018ZX09735-
002), Project of National Science Foundation of China (81803706) and the innovation program
of science and research from DICP, CAS (ZZBS201803 and DICP I201917).
Appendix A. Supplementary data
Supplementary data, experiment details and NMR and HRMS spectra associated with this
article can be found, in the online version.
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