Table 1 Structure–activity relationship investigation of triple FXR/PPARα/δ activators 6–41.

From: A triple farnesoid X receptor and peroxisome proliferator-activated receptor α/δ activator reverses hepatic fibrosis in diet-induced NASH in mice

    

EC50 [μM] (max. rel. act.)

ID

R1

R2

R3

PPARα

PPARδ

PPARγ

FXR

6

2-COOH

—

Naphth-2-yl

tox.

tox.

tox.

7 ± 1 (44 ± 3%)

7

2-CH2COOH

—

Naphth-2-yl

1.4 ± 0.1 (33 ± 1%)

> 10

1.7 ± 0.1 (17 ± 1%)

9.2 ± 0.2 (31 ± 1%)

8

3-COOH

—

Naphth-2-yl

0.15 ± 0.01 (11 ± 1%)

1.3 ± 0.1 (14 ± 1%)

1.6 ± 0.1 (17 ± 1%)

1.5 ± 0.2 (37 ± 1%)

5

3-CH2COOH

—

Naphth-2-yl

5 ± 1 (37 ± 3%)

4.9 ± 0.9 (34 ± 2%)

16 ± 1 (14 ± 1%)

2.5 ± 0.2 (21 ± 1%)

9

3-CH2CH2COOH

—

Naphth-2-yl

1.0 ± 0.2 (31 ± 2%)

0.65 ± 0.03 (28 ± 1%)

2.6 ± 0.3 (19 ± 2%)

2.6 ± 0.3 (20 ± 1%)

10

4-COOH

—

Naphth-2-yl

>30

>30

4.4 ± 0.9 (18 ± 2%)

1.0 ± 0.2 (23 ± 1%)

11

4-CH2COOH

—

Naphth-2-yl

>30

>30

>30

3.1 ± 0.3 (9.8 ± 0.4%)

12

4-CH2CH2COOH

—

Naphth-2-yl

>30

>30

>30

2.1 ± 0.1 (21 ± 1%)

13

3-OCH2COOH

—

Naphth-2-yl

10 ± 1 (35 ± 2%)

10 ± 1 (43 ± 4%)

19 ± 1 (11 ± 1%)

5 ± 1 (19 ± 1%)

14

3-NHCH2COOH

—

Naphth-2-yl

>30

3.5 ± 0.2 (83 ± 3%)

5.7 ± 0.1 (7.7 ± 0.1%)

1.3 ± 0.1 (31 ± 1%)

15

3-NHC(CH3)2COOH

—

Naphth-2-yl

1.7 ± 0.1 (71 ± 3%)

3.6 ± 0.2 (42 ± 1%)

5.1 ± 0.9 (18 ± 1%)

0.45 ± 0.01 (10 ± 1%)

16

3-CH2CH2COOH

3-CH3

Naphth-2-yl

6.2 ± 0.1 (31 ± 1%)

2.7 ± 0.3 (30 ± 1%)

7.1 ± 1.3 (6 ± 1%)

i.a.

17

3-CH2CH2COOH

4-CH3

Naphth-2-yl

1.7 ± 0.2 (67 ± 3%)

0.17 ± 0.02 (34 ± 1%)

1.4 ± 0.3 (21 ± 2%)

1.5 ± 0.1 (21 ± 1%)

18

3-CH2CH2COOH

5-CH3

Naphth-2-yl

0.80 ± 0.02 (25 ± 1%)

0.21 ± 0.01 (14 ± 1%)

3.3 ± 0.1 (23 ± 1%)

i.a.

19

3-CH2CH2COOH

6-CH3

Naphth-2-yl

7.4 ± 0.4 (15 ± 1%)

6.3 ± 0.9 (20 ± 1%)

11 ± 2 (2.5 ± 0.2%)

i.a.

20

3-CH2CH2COOH

4-Cl

Naphth-2-yl

3.0 ± 0.1 (16 ± 1%)

1.9 ± 0.2 (16 ± 1%)

1.4 ± 0.1 (6.0 ± 0.1%)

i.a.

21

3-CH2CH2COOH

4-OH

Naphth-2-yl

5.3 ± 0.5 (54 ± 3%)

2.4 ± 0.1 (34 ± 1%)

2.3 ± 0.3 (20 ± 2%)

4.5 ± 0.1 (16 ± 1%)

22

3-CH2CH2COOH

4-OCH3

Naphth-2-yl

0.30 ± 0.04 (43 ± 2%)

0.06 ± 0.01 (32 ± 1%)

1.3 ± 0.1 (27 ± 1%)

11 ± 3 (22 ± 1%)

23

3-CH2CH2COOH

4-OCF3

Naphth-2-yl

1.1 ± 0.3 (31 ± 4%)

0.38 ± 0.06 (30 ± 2%)

1.0 ± 0.2 (15 ± 1%)

1.1 ± 0.1 (12 ± 1%)

24

3-CH2CH2COOH

4-tBu

Naphth-2-yl

0.31 ± 0.08 (63 ± 8%)

0.27 ± 0.02 (25 ± 1%)

1.5 ± 0.1 (20 ± 1%)

0.30 ± 0.01 (13 ± 1%)

25

3-CH2CH2COOH

5-Cl

Naphth-2-yl

0.9 ± 0.2 (42 ± 2%)

0.28 ± 0.03 (17 ± 1%)

6 ± 1 (26 ± 2%)

2.6 ± 0.4 (12 ± 1%)

26

3-CH2CH2COOH

5-OH

Naphth-2-yl

8.9 ± 0.8 (28 ± 2%)

10 ± 2 (24 ± 2%)

13 ± 1 (9 ± 1%)

i.a.

27

3-CH2CH2COOH

5-OCH3

Naphth-2-yl

0.23 ± 0.04 (53 ± 2%)

0.36 ± 0.01 (23 ± 1%)

2.0 ± 0.1 (15 ± 1%)

i.a.

28

3-CH2CH2COOH

5-OCF3

Naphth-2-yl

0.21 ± 0.02 (54 ± 1%)

0.10 ± 0.01 (19 ± 1%)

1.1 ± 0.2 (18 ± 2%)

i.a.

29

3-CH2CH2COOH

4,5-Methylenedioxy

Naphth-2-yl

0.46 ± 0.03 (25 ± 1%)

0.4 ± 0.1 (31 ± 3%)

0.9 ± 0.3 (15 ± 2%)

2.9 ± 0.6 (14 ± 1%)

30

3-CH2CH2COOH

—

1,1'-Biphenyl-4-yl

>30

2.5 ± 0.5 (38 ± 4%)

1.6 ± 0.2 (16 ± 1%)

1.3 ± 0.2 (33 ± 1%)

31

3-CH2CH2COOH

—

4-(Furan-2-yl)phenyl

1.8 ± 0.3 (22 ± 1%)

0.20 ± 0.01 (43 ± 1%)

2.2 ± 0.1 (9 ± 1%)

5.4 ± 0.1 (23 ± 1%)

32

3-CH2CH2COOH

—

4-(Furan-3-yl)phenyl

1.6 ± 0.3 (31 ± 2%)

2.4 ± 0.2 (57 ± 3%)

4.2 ± 0.9 (38 ± 5%)

0.23 ± 0.01 (20 ± 1%)

33

3-CH2CH2COOH

—

4-(Thiophen-2-yl)phenyl

1.5 ± 0.1 (27 ± 1%)

0.64 ± 0.06 (35 ± 1%)

1.4 ± 0.2 (11 ± 1%)

1.7 ± 0.4 (21 ± 1%)

34

3-CH2CH2COOH

—

4-(Thiophen-3-yl)phenyl

1.7 ± 0.1 (32 ± 1%)

1.6 ± 0.3 (59 ± 5%)

1.3 ± 0.2 (17 ± 1%)

0.6 ± 0.1 (18 ± 1%)

35

3-CH2CH2COOH

—

4-(Isoxazol-3-yl)phenyl

8.0 ± 0.4 (11 ± 1%)

5.6 ± 0.4 (29 ± 1%)

5.8 ± 0.8 (30 ± 2%)

6.8 ± 0.6 (32 ± 1%)

36

3-CH2CH2COOH

—

4-(Isoxazol-4-yl)phenyl

Unstable

Unstable

Unstable

Unstable

37

3-CH2CH2COOH

—

4-(Oxazol-4-yl)phenyl

20 ± 1 (36 ± 3%)

12 ± 1 (52 ± 2%)

6 ± 1 (15 ± 1%)

6.9 ± 0.3 (41 ± 1%)

38

3-CH2CH2COOH

—

4-(Oxazol-5-yl)phenyl

> 30

12 ± 1 (32 ± 3%)

5.3 ± 0.2 (16 ± 1%)

15 ± 4 (53 ± 4%)

39

3-CH2CH2COOH

—

4-(1,2,3-Triazol-1-yl)phenyl

i.a.

i.a.

>30

i.a.

40

3-NHCH2COOH

4-OCH3

4-(Furan-3-yl)phenyl

>30

1.6 ± 0.1 (54 ± 2%)

7.7 ± 0.5 (9 ± 1%)

0.29 ± 0.01 (43 ± 1%)

41

3-CH2CH2COOH

4-tBu

4-(Furan-2-yl)phenyl

0.17 ± 0.04 (72 ± 5%)

0.14 ± 0.01 (34 ± 1%)

2.4 ± 0.1 (16 ± 1%)

0.015 ± 0.002 (19 ± 1%)

  1. Results are expressed as the mean ± SEM; n = 3. Maximum relative activation (max. rel. act.) refers to the activity of reference compounds GW7647 (PPARα), rosiglitazone (PPARγ), L165,041 (PPARδ) at 1 µM, and GW4064 (FXR) at 3 µM.
  2. i.a. inactive at 10 μM, tox. toxic at 30 μM.
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