Free fatty acid receptor 1 (FFA1/GPR40) agonists: Mesylpropoxy appendage lowers lipophilicity and improves ADME properties

Article abstract of DOI:10.1021/jm3002026

FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic stability while preserving potency, resulting in discovery of the potent FFA1 agonist 13.

Full text of DOI:10.1021/jm3002026

Brief Article
pubs.acs.org/jmc
Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists: Mesylpropoxy
Appendage Lowers Lipophilicity and Improves ADME Properties
Elisabeth Christiansen,† Maria E. Due-Hansen,† Christian Urban,‡ Manuel Grundmann,§ Ralf Schroder,§
̈
Brian D. Hudson,∥ Graeme Milligan,∥ Michael A. Cawthorne,⊥ Evi Kostenis,§ Matthias U. Kassack,‡
and Trond Ulven*,†
†Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark
‡Institute of Pharmaceutical and Medicinal Chemistry, University of Dusseldorf, Universitatsstrasse 1, D-40225 Dusseldorf, Germany
̈
̈
̈
§Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115 Bonn, Germany
∥Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences,
University of Glasgow, Glasgow G12 8QQ, Scotland, U.K.
⊥Clore Laboratory, University of Buckingham, Hunter Street, Buckingham MK18 1EG, U.K.
S
* Supporting Information
ABSTRACT: FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist
TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The
appendage significantly lowers lipophilicity and improves metabolic stability while preserving potency, resulting in discovery of
the potent FFA1 agonist 13.
a
Chart 1. Representative FFA1 Agonists
INTRODUCTION
■
Current methods used for design, synthesis, screening, and
optimization in drug discovery tend to produce compounds
with higher than ideal lipophilicity, a property that recently has
been repeatedly pointed at as a critical factor for the success of
new potential drugs in the development stages because high
lipophilicity is associated with poor absorption, metabolic
instability, high promiscuity, toxic effects, and consequently a
higher risk of attrition in clinical trials.1−7 To counteract this,
concepts such as ligand efficiency (LE, free energy binding
divided by the number of non-hydrogen atoms),8 ligand
lipophilicity efficiency (LLE, logarithmic potency subtracted by
log P or log D)1 and ligand efficiency-dependent lipophilicity
(LELP, log P divided by LE)7 have been introduced and are
increasingly being implemented in drug discovery programs
and useful in directing optimization away from oversized and
highly lipophilic compounds.
a
ClogP is calculated by ChemBioDraw.
The free fatty acid receptor 1 (FFA1, also known as GPR40)
is activated by medium- and long-chain free fatty acids (FFAs),
is highly expressed on pancreatic β-cells, and enhances glucose-
stimulated insulin secretion.9−11 This observation has attracted
considerable attention to the receptor as a new potential target
for improved therapeutics for treatment of type 2 diabetes, and
several potent and selective FFA1 agonists are now known
(Chart 1).12−26 Many of these ligands have relatively high
lipophilicity, most likely resulting from fatty acids being used as
initial leads and from the lipophilic nature of the FFA1 binding
site. We recently addressed this issue in our alkyne series, where
we were able to lower the lipophilicity of the compounds by
replacing the terminal benzene ring by aromatic nitrogen
containing heterocycles (cf. TUG-499 in Chart 1).22
namic acid (TUG-20) in screening of a focused library of
constrained FFA analogues.19 Inspired by the subsequent
publication of the related potent FFA1 agonist GW9508,12 we
explored the structure−activity relationships (SAR) around
these compounds and found that whereas the central ether is
favored for small compounds, a central amine is preferred when
the structures are more extended such as for GW9508 and
TUG-469.19 The central amine has the additional advantage
that it provides less lipophilic compounds. Takeda recently
published their clinical candidate TAK-875, corresponding to a
conformationally constrained analogue of TUG-469 with an
In our program aimed at discovery of potent and selective
FFA1 (GPR40) agonists, we identified 4-benzyloxydihydrocin-
Received: February 14, 2012
Published: June 25, 2012
© 2012 American Chemical Society
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Journal of Medicinal Chemistry
Brief Article
additional ortho-methyl and a para-mesylpropoxy chain on the
biphenyl system and furthermore contains a central ether linker
rather than the amine linker predicted by our SAR studies
(Chart 1).18 Calculations indicated that the mesylpropoxy
appendage decrease lipophilicity by an order of magnitude. As
the ClogP of 5 is in the uppermost part of the generally
acceptable range, we were interested in exploring the effects of
introducing a mesylpropoxy chain on this compound.
prepared by a Heck coupling of 1 with ethyl acrylate followed
by ester hydrolysis. Reductive amination of 2 with 2′-
methylbiphenyl-3-carboxaldehyde followed by hydrogenation
of the double bond over palladium provided 10 but in very
poor yield (see Supporting Information (SI)). By swapping the
first two steps and reducing 2 to 3a followed by reductive
coupling with 4d, 4e, and 4b, compounds 11−13 were
obtained, respectively, in moderate to good overall yields
(Scheme 1).
In our assay, 5 is somewhat more potent than 6 (racemic
TAK-875) but also more lipophilic, giving 6 a slightly higher
LLE (Table 1). The potency of EC50 = 26 nM found for 6 is in
excellent agreement with the activity reported by Takeda for
TAK-875 (EC50 = 14 nM), given that this enantiomer is
primarily responsible for the activity.18 Takeda has also
reported the racemic analogue of TAK-875 lacking the
mesylpropoxy substituent to have pEC50 = 7.66, i.e., equipotent
with TAK-875 when it is taken into account that one
enantiomer is mainly responsible for the activity.18 Thus, the
mesylpropoxy tail appears to improve ADME properties by
lowering lipophilicity rather than to increase potency.
We proceeded by attaching a corresponding mesylpropoxy
tail to 5. The resulting 7 indeed turned out equipotent with 5
but had lipophilicity reduced by one log unit and thereby
obtained a significant advantage in terms of LLE. Introducing
the second ortho-methyl group in the biphenyl system (8)
resulted in a barely significant increase in potency and a drop in
LLE due to increased lipophilicity.
RESULTS AND DISCUSSION
■
Compounds 5, 6, and 9 were synthesized as described
previously.18−20 The mesylpropoxy-appended analogues 7 and
8 were synthesized as described for 519 using the
mesylpropoxy-substituted biphenyl building blocks 4b and
4c18 (Scheme 1). The 2-fluoro substituted intermediate 3a was
a
Scheme 1
The values for 6−8 in Table 1 are in the presence of 0.05%
BSA. In the absence of BSA, the values were significantly lower
(pEC50 6.85 0.04 for 6, 7.46 0.06 for 7, and 7.52 0.04 for
8). BSA often reduces the observed potency by competitive
binding of the ligand but can also increase potency by
increasing solubility, presumably the explanation of the effects
observed here.27
The precursor in the development of TAK-875 is the highly
potent and lipophilic 9 (Cmp 4p in Chart 1), which differs
from 5 in having a second ortho-methyl substituent on the
biphenyl system, a central ether linker, and a 2-fluoro
a
Reagents, conditions and yields: (a) ethyl acrylate, Pd(OAc)2, P(o-
tolyl)3, DIPEA, DMF, 80 °C, 4 h, 86%; (b) LiOH, THF, MeOH, H2O,
rt, 3 d, 99%; (c) Pd/C, MeOH, H2, rt, 2 h, 73%; (d) NaBH(OAc)3,
CH2Cl2, AcOH (cat.), rt, 3−21 h, 38−67%.
Table 1. Effects of para-Mesylpropoxy Chain and Substituents on FFA1 Agonist Activity and Lipophilicity
FFA1 pEC
GPR120 pEC50
5a0
b
c
d
e
R1
R2
R3
R4
H
X
(% efficacy)
(% efficacy)
LogD7.4 (ClogP)
LE
LLE
HLM (%)
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Et
H
H
NH
O
7.73 0.04 (114)
5.20 0.02 (53)
2.49 0.01 (4.9)
2.24 0.03 (4.7)
1.43 0.01 (3.9)
1.77 0.02 (4.4)
3.82 0.13 (6.2)
2.86 0.03 (5.4)
2.88 0.01 (5.9)
3.03 0.04 (5.6)
1.87 0.01 (4.4)
0.41
0.28
0.31
0.31
0.37
0.41
0.37
0.38
0.32
5.2 (2.8)
5.4 (2.9)
6.3 (3.8)
6.1 (3.7)
3.6 (1.3)
5.2 (2.7)
4.8 (1.7)
4.7 (2.2)
6.2 (3.7)
87
101
106
f
g
h
Me
H
MsC3H6O
7.59 0.04 (91)
n.t.
g
MsC3H6O
H
H
F
NH
NH
O
7.76 0.03 (98)
4.96 0.07 (90)
g
h
Me
Me
H
MsC3H6O
7.83 0.04 (92)
n.t.
i
H
7.46 0.04 (92)
8.03 0.04 (102)
7.63 0.02 (101)
7.75 0.02 (104)
8.04 0.02 (102)
5.08 0.08 (82)
5.07 0.04 (92)
5.37 0.08 (91)
4.03 0.08 (78)
4.36 0.09 (66)
42
10
11
12
13
H
F
NH
NH
NH
NH
H
H
F
Me
Me
Me
H
H
F
MsC3H6O
F
100
a
b
Efficacy is given as percentage of the full agonist TUG-20.19 LogD7.4 values were determined by shake-flask procedure. ClogP values were
c
calculated by the BioByte’s algorithm as implemented in ChemBioDraw Ultra 12.0 (the “ClogP” option). LE values were calculated by −Δg = RT ln
KD, presuming EC50 ≈ KD.8 LLE values were calculated by the formula pEC50 − LogD7.4 (values in parentheses were calculated by pEC50 − ClogP).
d
e
f
Stability toward human liver microsomes (HLM) was evaluated at Cerep Inc. (see the SI) Racemic TAK-875 (structure in Chart 1). The pure (S)-
g
h
enantiomer is previously reported by Takeda as with EC50 = 14 nM (pEC50 = 7.85) in a FLIPR assay with 0.1% BSA. Tested with 0.05% BSA. Not
tested. Previously reported by Takeda as an FFA1 agonist with EC50 = 5.7 nM (pEC50 = 8.22) in a FLIPR assay with 0.1% BSA.
i
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Figure 1. Activity of 13 on FFA1 transfected HEK293 cells and on the rat β-cell line INS-1E. (A) Representative traces (mean + SEM) from the
dynamic mass redistribution (DMR) assay of HEK293 cells stably expressing the human FFA1 receptor (FFA1-HEK) and stimulated with the
indicated concentrations of 13. (B) Receptor activation in FFA1-HEK cells is concentration-dependent (pEC50: 7.34 0.06, n = 3); no activation is
detectable in native HEK293 cells. (C) Representative traces from the DMR assay of INS-1E cells endogenously expressing FFA1. (D)
Concentration-effect-curve of 13 on INS-1E cells (pEC50 = 6.74 0.14, n = 6). Preincubation with the FFA1 antagonist TUG-76122 (30 μM)
resulted in a right-shifted curve (pEC50 = 5.71 0.21, n = 3), confirming FFA1-dependent DMR responses.
substituent on the central benzene ring.20 The compound
surprisingly appeared significantly less potent in our assay than
reported by Takeda. It is possible that the difference is related
to Takeda using 0.1% BSA in the assay. We wished to explore
the ortho-fluoro substituent, which was introduced by the
Takeda group to resolve metabolic issues with preceding
compounds but which also was found to slightly increase
potency. Introducing the 2-fluoro substituent on 5 to give 10
indeed boosted potency to the single-digit nanomolar range but
also increased lipophilicity correspondingly, leading to virtually
unchanged or slightly decreased LE and LLE. Substituting the
ortho-methyl for ethyl (11) gave a significant decrease in
potency and a similar increase in lipophilicity. Surprisingly, a
second ortho-methyl substituent (12) also resulted in decreased
potency.
In an attempt to reach an optimal combination of high
potency and moderate lipophilicity, the 2-fluoro substituent and
the mesylpropoxy chain were introduced to 10 to give 13.
Again, whereas the two compounds exhibited identical potency,
lipophilicity (ClogP and logD7.4) was lowered by an order of
magnitude. Despite the LE of 13 being significantly lower than
5 and 10 and that the compound exhibits an LLE value similar
to 7 and 8, we believe that 13 represents the optimal
combination of high potency and acceptable lipophilicity in this
series. In contrast to the other compounds with mesylpropoxy
appendages, the potency of 13 was not affected by 0.05% BSA.
Lipophilicity is known to influence the metabolic stability by
increasing interaction with enzymes. We found that 6 (racemic
TAK-875), 7, and 13 all were completely stable toward human
liver microsomes, whereas the somewhat more lipophilic
compound 5 had slightly reduced stability (Table 1). The
significantly reduced stability of 9 (Chart 1) is in agreement
with the higher lipophilicity of the compound.24
Likewise, 13 induced a concentration dependent response in
insulin secreting rat β-cell line INS-1E endogenously expressing
FFA1. Pretreatment with the FFA1 antagonist TUG-76122
resulted in a right-shifted curve, and pretreatment with the
selective FFA1 agonist TUG-499 (Chart 1 and ref 22)
prevented activation by 13 (Figure S1, SI), demonstrating
that the activity is mediated through FFA1. 13 was devoid of
activity on the related receptors FFA2 and FFA3 (Figure S2,
SI) and on nontransfected HEK293 cells in the DMR assays
(Figure 1) and exhibited 4800-fold selectivity over GPR120, an
order of magnitude higher than 5 (Table 1).
The pharmacokinetic properties of compounds 5 and 13
were investigated in mice. Both compounds were rapidly
absorbed, and compound 13 exhibited twice as high exposure
as 5 (Table 2). This effect can be rationalized by reduced first-
pass metabolism due to the lower lipophilicity of 13.
a
Table 2. Pharmacokinetic Parameters after Oral Dosing
Cmax (ng/mL)
Tmax (min)
AUCpo (ng·h/mL)
5
2360
8748
15
15
2740
5202
13
a
Compounds were dosed p.o. at 10 mg/kg in mice (n = 3).
CONCLUSION
■
By combining features of the previously published compounds
5, 6, and 9, we identified 13 as a compound with higher
potency and lower lipophilicity than any previous FFA1
agonist. The 2-fluoro substituent increases both potency and
lipophilicity by approximately the same degree and is therefore
only an advantage as long as the compound is not already too
lipophilic. The mesylpropoxy chain decreased lipophilicity by
one log unit without affecting potency on FFA1. A
consequence of the reduced lipophilicity was increased stability
toward human liver microsomes. It seems possible that
attachment of mesylalkoxy or similar groups can represent a
general strategy for lowering the lipophilicity and thereby
Compound 13 was examined further using a dynamic mass
redistribution (DMR) assay, enabling real-time label-free
detection of intracellular events.28 Concentration dependent
activation of hFFA1 transfected HEK293 cells was confirmed,
with no detectable activity on native HEK293 cells (Figure 1).
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(13). A dry flask charged with 2′-methyl-4′-(3-(methylsulfonyl)-
propoxy)-[1,1′-biphenyl]-3-carbaldehyde (4b, 35 mg, 0.11 mmol), 3-
(4-amino-2-fluorophenyl)propanoic acid (3a, 19 mg, 0.11 mmol),
CH2Cl2 (1 mL) and AcOH (1 drop) under argon was added
NaBH(OAc)3 (34 mg, 0.16 mmol) and stirred at room temperature
until consumption of the starting material. The reaction mixture was
quenched with water and aqueous HCl (1 M), and extracted with
CH2Cl2. The combined organic phases were washed with brine, dried
over (MgSO4), and concentrated. The residue was purified by flash
chromatography (SiO2, EtOAc:petroleum ether, 1:2) to give 30 mg
(58%) of 13 as a light-brown foam; Rf = 0.54 (EtOAc) (purity 98.1%
“rescuing” otherwise problematic compound series. The
viability of this strategy is currently being explored on other
compound series.
EXPERIMENTAL SECTION
■
All commercial starting materials and solvents were used without
further purification unless otherwise stated. THF was freshly distilled
from sodium/benzophenone. DIPEA was dried over 4 Å sieves, and
anhydrous DMF was purchased from Sigma-Aldrich. Purification by
flash chromatography was carried out using silica gel 60 (0.040−0.063
1
1
mm, Merck). H and 13C NMR spectra were recorded at 400 MHz
by HPLC). H NMR (acetone-d6) δ 7.40−7.29 (m, 3H), 7.22−7.07
(m, 2H), 7.05−6.94 (m, 1H), 6.90−6.78 (m, 2H), 6.48−6.32 (m, 2H),
4.40 (s, 2H), 4.18 (t, J = 6.1 Hz, 2H), 3.35−3.26 (m, 2H), 2.99 (s,
3H), 2.77 (t, J = 7.7 Hz, 2H), 2.49 (t, J = 7.7 Hz, 2H), 2.34−2.19 (m,
2H), 2.18 (s, 3H). 13C NMR (acetone-d6) δ 174.3, 163.8 (d, J = 241.4
Hz), 158.9, 150.1 (d, J = 11.1 Hz), 142.6, 140.7, 137.4, 135.5, 131.7 (d,
J = 8.1 Hz), 131.5, 129.1, 128.6, 126.4, 117.3, 115.5 (d, J = 16.2 Hz),
112.7, 109.7 (d, J = 2.0 Hz), 100.0 (d, J = 26.3 Hz), 66.6, 52.0, 48.0,
40.8, 30.1, 24.5 (d, J = 2.0 Hz), 24.5, 23.5, 20.8. ESI-MS calcd for
C27H30FNO5SNa (M + Na+), 500.1901; found, 500.1916.
and 101 MHz, respectively, and calibrated relative to TMS internal
standard or residual solvent peak. High-resolution mass spectra
(HRMS) were obtained on a Bruker micrOTOF-Q II (ESI). HPLC
analysis was performed using a Dionex 120 C18 column (5 μ, 4.6 ×
150 mm2); flow, 1 mL/min; 10% acetonitrile in water (0−1 min), 10−
100% acetonitrile in water (1−10 min), 100% acetonitrile (11−15
min), with both solvents containing 0.05% TFA as modifier; UV
detection at 254 nm. Purity was determined by HPLC analysis and
confirmed by inspection of NMR spectra. All target compounds have
>95% purity.
ASSOCIATED CONTENT
(E)-3-(4-Amino-2-fluorophenyl)acrylic Acid (2). Step 1: A dry
Schlenk flask was charged with 4-bromo-3-fluoroaniline (1140 mg,
6.01 mmol), Pd(OAc)2 (67 mg, 0.30 mmol), tris(2-methylphenyl)-
phosphine (182 mg, 0.60 mmol), DMF (4.2 mL), and DIPEA (4.2
mL) under N2-flow. The flask was evacuated and backfilled with argon
before addition of ethyl acrylate (0.8 mL, 7.36 mmol) and heated to 80
°C for 4 h. The reaction was cooled to room temperature, added
water, and extracted with EtOAc. The organic phase was washed with
water and brine, dried (MgSO4), and concentrated. The residue was
purified by flash chromatography (SiO2, EtOAc:petroleum ether, 1:2)
to give ethyl 4-amino-2-fluorocinnamate (1079 mg, 86%) as a yellow
■
S
* Supporting Information
Synthetic procedures and compound characterization, proce-
dures for logD7.4 determination and biological assays. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: +45 6550 2568. Fax: +45 6615 8780. E-mail: ulven@
sdu.dk.
1
solid; Rf = 0.19 (EtOAc:petroleum ether, 1:2). H NMR (CDCl3) δ
7.71 (d, J = 16.1 Hz, 1H), 7.31 (t, J = 8.3 Hz, 1H), 6.42 (dd, J = 8.4
Hz, 2.3 Hz, 1H), 6.35 (dd, J = 12.6 Hz, 2.1 Hz, 1H), 6.32 (d, J = 16.1
Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.08 (s, 2H), 1.32 (t, J = 7.1 Hz,
3H). 13C NMR (CDCl3) δ 167.6, 162.8 (d, J = 253.5 Hz), 150.2 (d, J
= 12.1 Hz), 137.7 (d, J = 2.4 Hz), 130.4 (d, J = 5.1 Hz), 116.0 (d, J =
7.1 Hz), 112.5 (d, J = 13.1 Hz), 110.9 (d, J = 2.0 Hz), 101.6 (d, J =
26.3 Hz), 60.3, 14.3. Step 2: A solution of ethyl 4-amino-2-
fluorocinnamate (1002 mg, 4.79 mmol) in THF (32 mL) was added
to a solution of LiOH·H2O (567 mg, 20.0 mmol) in H2O (16 mL),
and MeOH (5 mL) was added to give a homogeneous solution. The
reaction was stirred at room temperature until complete hydrolysis,
then added aqueous HCl (1 M) until pH <2 and extracted with EtOAc
(×3). The combined organic phases were washed with brine, dried
(MgSO4), and concentrated to give 858 mg (99%) of 2 as an orange
solid; tR = 8.03 min (HPLC). 1H NMR (MeOH-d4) δ 7.70 (d, J = 16.0
Hz, 1H), 7.36 (t, J = 8.5 Hz, 1H), 6.48 (dd, J = 8.5 Hz, 2.2 Hz, 1H),
6.38 (dd, J = 13.5 Hz, 2.2 Hz, 1H), 6.26 (d, J = 16.0 Hz, 1H), 4.91 (s,
2H). 13C NMR (MeOH-d4) δ 171.4, 164.5 (d, J = 250.5 Hz), 154.5 (d,
J = 13.3 Hz), 139.9 (d, J = 3.0 Hz), 131.3 (d, J = 5.1 Hz), 115.1 (d, J =
7.1 Hz), 111.8 (d, J = 1.8 Hz), 111.5 (d, J = 12.1 Hz), 101.3 (d, J =
26.3 Hz).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Lone Overgaard Storm for excellent technical
support, Corning and Perkin-Elmer for instrument support, and
the Danish Council for Independent Research|Technology and
Production (grant 09-070364) and the Danish Council for
Strategic Research (grant 11-116196) for financial support.
ABBREVIATIONS USED
■
ADME, absorption distribution metabolism excretion; AUC,
area under the curve; BSA, bovine serum albumin; DIPEA,
diisopropylethylamine; DMR, dynamic mass redistribution;
FFA, free fatty acid; FFA1, free fatty acid receptor 1 (GPR40);
HEK, human embryonic kidney; SAR, structure−activity
relationships
3-(4-Amino-2-fluorophenyl)propanoic Acid (3a). To a sol-
ution of 2 (388 mg, 2.14 mmol) in MeOH (15 mL) was added 10%
Pd/C (35 mg). The reaction mixture was placed under argon, the
argon was replaced with H2, and the reaction mixture was stirred under
ambient pressure. After 2 h, the reaction mixture was filtered through
Celite, concentrated, and purified by flash chromatography (SiO2,
EtOAc) to give 3a (285 mg, 73%) as a pale-brown solid; tR = 4.88 min
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