Discovery of TUG-770: A highly potent free fatty acid receptor 1 (FFA1/GPR40) agonist for treatment of type 2 diabetes

Article abstract of DOI:10.1021/ml4000673

Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing.

Full text of DOI:10.1021/ml4000673

Letter
pubs.acs.org/acsmedchemlett
Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1
(FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes
Elisabeth Christiansen,† Steffen V. F. Hansen,† Christian Urban,‡ Brian D. Hudson,§ Edward T. Wargent,∥
Manuel Grundmann,⊥ Laura Jenkins,§ Mohamed Zaibi,∥ Claire J. Stocker,∥ Susanne Ullrich,#
Evi Kostenis,⊥ Matthias U. Kassack,‡ Graeme Milligan,§ Michael A. Cawthorne,∥ 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 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.
⊥Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115 Bonn, Germany
#Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical
Chemistry, University of Tubingen, Otfried-Muller-Str. 10, 72076 Tubingen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Free fatty acid receptor 1 (FFA1 or GPR40) enhances
glucose-stimulated insulin secretion from pancreatic β-cells and currently
attracts high interest as a new target for the treatment of type 2 diabetes.
We here report the discovery of a highly potent FFA1 agonist with
favorable physicochemical and pharmacokinetic properties. The com-
pound efficiently normalizes glucose tolerance in diet-induced obese mice,
an effect that is fully sustained after 29 days of chronic dosing.
KEYWORDS: Type 2 diabetes, free fatty acid receptor, TUG-770, insulin secretagogue, FFA1 agonist, GPR40 agonist
he free fatty acid receptor 1 (FFA1, previously known as
GPR40) has, since its deorphanization in 2003, received
corresponding 4-bromoaldehydes (Scheme 1). Initially, a
Wittig reaction with the phosphonium ylide, formed in situ
from ethyl bromoacetate and triphenylphosphine, provided the
corresponding cinnamic esters. The double bond was reduced
by NaBH4 in the presence of catalytic CoCl2.11 Subsequently,
Sonogashira coupling with phenylacetylene followed by a base
promoted hydrolysis provided the alkyne ligands.12
The 2-fluoro substituted ligands were synthesized from the
central intermediate 2, prepared from aryl bromide 1 by an initial
Sonogashira coupling with trimethylsilylacetylene and subsequent
removal of the TMS-group (Scheme 2). A second Sonogashira
coupling of 2 with various aryl halides followed by ester hydrolysis
gave the alkyne ligands in moderate to high yields.
We set out to investigate modifications in the central ring of
the alkyne ligands (Table 1). Compounds were tested on the
human FFA1 in a calcium mobilization assay and coun-
terscreened on the human FFA4 (previously GPR120)13
because of the selectivity issues frequently observed for these
receptors.14 The central benzene ring was replaced by pyridine
due to its marked lipophilicity lowering effect. The 2-pyridyl
T
considerable attention as a new potential target for treatment
of type 2 diabetes (T2D).1−3 Activation of FFA1 increases
glucose-stimulated insulin secretion but does not affect insulin
secretion at low glucose levels, providing a potentially safe and
efficient strategy for enhancing insulin levels in patients
suffering from T2D. Accordingly, the interest in FFA1 as a
new drug target has been high, and several potent agonists for
the receptor have been disclosed.4−6 Of these, TAK-875 is most
advanced with highly encouraging results from phase II clinical
trials.7 Being a fatty acid receptor, FFA1 has a natural
preference for relatively lipophilic compounds. This property
has been reflected in the majority of the reported synthetic
agonists, which mostly have been at the high end of the
generally recommended lipophilicity range. We have previously
reported a series of alkyne FFA1 agonists8 and have
subsequently directed our efforts toward lowering the lip-
ophilicity of these compounds.9,10 Herein, we report the further
optimization of this compound series, leading to a highly potent
FFA1 agonist with excellent physicochemical and pharmacoki-
netic properties and sustained glucose lowering capability in
diet-induced obese (DIO) mice after acute and chronic dosing.
The alkyne ligands with either pyridine or fluoro-substituted
benzene as the central ring were synthesized from the
Received: February 17, 2013
Accepted: April 8, 2013
© XXXX American Chemical Society
A
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a
Scheme 1
Table 1. SAR Investigations of the Central Ring
a
Reagents and conditions: (a) ethyl bromoacetate, PPh3, NaHCO3,
water, EtOAc, room temp, 18 h, 87−96%; (b) CoCl2·6H2O, NaBH4,
MeOH, 0 °C → room temp, 3 h, 59−87%; (c) PhCCH, Na2PdCl4, 2-
(di-tert-butylphosphino)-1-phenylindole (PIntB), CuI, TMEDA,
water, 70 → 80 °C, 0.5−4.5 h, 56−86%; (d) LiOH, THF, water,
room temp, 12 h, 79−97%.
a
Scheme 2
a
b
Efficacy is given as % response relative to 10 μM TUG-20.19 Efficacy
is given as % response relative to 9; n.a. = no activity (pEC50 < 4).14
c
Calculated by BioByte’s algorithm as implemented in ChemBioDraw
d
Ultra 12.0 (ClogP option). LE = RTln KD, presuming that EC50
≈
KD. Values are given in kcal mol−1 per non-hydrogen atom.17 LLE =
pEC50 − ClogP.18
a
Reagents and conditions: (a) trimethylsilylacetylene, Na2PdCl4,
previous SAR information is not directly transferrable to the
2-fluoro series.
PIntB, CuI, TMEDA, water, 70 → 80 °C, 10 min; (b) K2CO3,
MeOH, room temp, 2 h, 74% over two steps; (c) aryl halide,
Na2PdCl4, PIntB, CuI, TMEDA, water, 80 °C, 1−4 h, 52−70%; (d)
LiOH, THF, water, room temp, 12 h, 69−100%.
Introduction of a cyano-substituent on 10 to give the
2-methyl-5-cyano analogue (12) resulted in reduced ClogP
together with doubled potency and increased selectivity over
FFA4. The difluoromethyl analogue (13) was found to be more
potent than 10 but only equipotent with 12, despite its higher
lipophilicity. The 3,5-dichloro analogue (14) was synthesized to
mimic the previously published chloro-substituted pyridine
alkyne TUG-4999 but turned out only equipotent with TUG-
499, despite its high lipophilicity.
Extension of the ortho- and meta-methyl with the hydrophilic
mesyl group was explored (15 and 16) and resulted in
significantly reduced ClogP values and improved LLE but
unfortunately also markedly reduced potency. Methoxymethyl
substituents on the terminal ring have previously shown good
potency and significantly reduced lipophilicity in the alkyne
series.10 When adding larger substituents on the terminal
ring of the alkyne ligands, the meta-substituted compounds
(18 and 20) were found to be favored over the ortho analogues
(17 and 19). Although all four analogues exhibited high
selectivity over FFA4, the potency was found to be rather low
(EC50 = 0.3−0.7 μM).
(4) and 3-pyridyl (5) analogues turned out to be twice as
potent as previously reported ligands with pyridines as the
terminal ring9 but, nevertheless, resulted in >20-fold decrease in
potency compared to 3. Aromatic fluoro-substituents often
result in higher metabolic stability and have been applied with
success in the corresponding ring of other compound
series.15,16 Thus, we selected three mono- and difluoro-
substituted analogues for synthesis and testing. The 3-fluoro
analogue (6) showed maintained potency and only a small
increase in ClogP compared to 3. The 2-fluoro analogue (7)
resulted in a 5-fold increased potency and the highest ligand
efficiency (LE)17 and ligand lipophilicity efficiency (LLE)18
values and, moreover, the highest selectivity over FFA4 (>200-
fold). Introduction of a second ortho-fluoro substituent (8) led
to a reduction of potency back to the level of 6 and 3.
With 7 showing high potency and LE, we decided to focus
on the 2-fluoro scaffold in the exploration of the terminal ring
in analogy with our previous studies (Table 2). Introduction of
a corresponding 2-fluoro substituent in the lead structure
TUG-424 (9) to give 10 resulted in increased potency but
less so than for the terminally unsubstituted pair 3 and 7
(ΔpEC50 = 0.14 vs 0.78). Moving the methyl of the terminal
ring to the meta-position (11) gave a further increase in
potency. The order of potency is thus reversed relative to the
analogues lacking the 2-fluoro substituent,8 implying that
We then directed our attention to the cyanomethyl alkyne
TUG-488 (21).10 The corresponding 2-fluoro analogue 22
(TUG-770) showed a pronounced increase in potency on
FFA1 (ΔpEC50 = 0.51) with EC50 = 6 nM and 150-fold selec-
tivity over FFA4. Moving the cyanomethyl to the meta-position
(23), which had been beneficial for the methyl analogue (11),
led to 12-fold erosion of potency. Finally, homologation to the
B
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ACS Medicinal Chemistry Letters
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Table 2. Structure−Activity Investigations of the 2-Fluoro Alkyne Agonists
pEC50 (efficacy, %)
a
b
c
d
e
compd
R1
X
hFFA1, calcium
hFFA4, BRET
ClogP
LE
LLE
9
2-Me
2-Me
3-Me
2-Me, 5-CN
2-CF2H, 5-F
3,5-Cl
H
F
F
F
F
F
F
F
F
F
F
F
H
F
F
F
7.34 0.07 (103)
7.48 0.03 (107)
7.65 0.03 (100)
7.77 0.03 (104)
7.74 0.04 (97)
7.42 0.07 (99)
5.84 0.02 (97)
5.71 0.02 (104)
6.21 0.03 (94)
6.44 0.03 (93)
6.14 0.04 (92)
6.43 0.04 (83)
7.70 0.04 (103)
8.21 0.03 (102)
7.13 0.03 (104)
7.74 0.04 (97)
b
5.84 0.01 (103)
5.80 0.03 (98)
5.41 0.07 (124)
5.02 0.04 (123)
5.93 0.04 (117)
5.50 0.25 (90)
n.a.
4.19 0.06 (26)
n.a.
n.a.
5.04
5.18
5.18
4.62
5.02
6.11
2.67
2.67
3.33
3.33
3.59
3.59
3.96
4.11
4.11
4.25
0.50
0.49
0.50
0.46
0.44
0.46
0.33
0.33
0.31
0.33
0.30
0.31
0.48
0.49
0.42
0.44
2.30
2.30
2.47
3.15
2.72
1.31
3.17
3.04
2.88
3.11
2.55
2.84
3.76
4.10
3.02
3.50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2-CH2Ms
3-CH2Ms
2-CH2O(CH2)2Ms
3-CH2O(CH2)2Ms
2-CH2O(CH2)3Ms
3-CH2O(CH2)3Ms
2-CH2CN
2-CH2CN
3-CH2CN
2-CH2CH2CN
n.a.
n.a.
6.11 0.06 (99)
6.03 0.06 (98)
5.41 0.07 (115)
5.86 0.00 (114)
Efficacy is given as % response relative to 10 μM TUG-20.19 Efficacy is given as % response relative to 9; n.a. = no activity (pEC50 < 4).14
a
c
d
Calculated by BioByte’s algorithm as implemented in ChemBioDraw Ultra 12.0 (ClogP option). LE = RTln KD, presuming that EC50 ≈ KD. Values
are given in kcal mol−1 per non-hydrogen atom.17 LLE = pEC50 − ClogP.18
e
corresponding cyanoethyl (24) resulted in good potency but
the compound could not compete with 22.
Table 3. Physicochemical Properties, in Vitro ADME, and
Pharmacokinetics of 21 and 22
With 22 being the clearly superior agonist in terms of
potency and LLE, as well as displaying significantly higher
physicochemical properties
21
196 μM
22
197 μM
99.1%
a
aqueous solubility (PBS, pH 7.4)
potency (EC50 = 6 vs 14 nM), lower lipophilicity (log D7.4
=
chemical stab. (PBS, 37 °C, 12 days) 99.8%
1.41 vs 2.24) and higher ligand efficiency (LE = 0.49 vs 0.29)
compared to the most advanced compound in the field TAK-
875,20 we set out to evaluate the compound further using our
previously preferred compound 21 as reference (Table 3).
Compound 22 displayed excellent physicochemical and in vitro
ADME properties, with good aqueous solubility, good chemical
stability, low lipophilicity, and decreased plasma protein
binding (PPB). In support of the lower PPB, 21 showed
significantly decreased activity on hFFA1 in a BRET assay in
the presence of 0.1% BSA (from 7.16 0.09 to 6.62 0.05, p =
0.0024), whereas the corresponding reduction of activity for 22
was insignificant (from 7.64 0.09 to 7.58 0.06, p = 0.5635).
Compound 22 furthermore showed excellent stability toward
human liver microsomes (HLM), no inhibition of selected
CYP-enzymes implicated in drug−drug interactions, no
P-glycoprotein (P-gp) inhibition, and good permeability in
the Caco-2 cell assay. Pharmacokinetic studies in mice showed
a fast oral absorption, higher plasma concentration, a longer
half-life, lower clearance, and increased bioavailability, overall
giving a markedly improved pharmacokinetic profile compared
to 21. No cytotoxicity was observed in vitro in up to 100 μM
concentration (see the Supporting Information), and no adverse
effects were seen in mice after four weeks of daily oral treatment
of 20 mg/kg and acute treatment in doses up to 250 mg/kg.
In addition to the counterscreen on FFA4, 22 showed a high
selectivity over FFA2, FFA3, PPARγ, and 54 diverse receptors,
transporters, and enzymes (see the Supporting Information).
The compound exhibited lower potency on the rodent orthologs
(mFFA1, pEC50 = 6.83 0.07 (n = 3); rFFA1, pEC50 = 6.49
0.05 (n = 2)). The effect of 22 was initially evaluated in vitro in
b
log D (n-octanol/PBS, pH 7.4)
in vitro ADME properties
1.28 (1.32)
1.35 (1.44)
c
PPB (human)
>99.9%
81%
97.3%
87%
metabolic stability (HLM)
CYP inhibition (10 μM)
CYP1A2
CYP2C9
CYP2C19
−3%
11%
−2%
5%
−10%
−33%
−5%
−1%
−1%
CYP2D6
CYP3A4
8%
P-gp inhibition (% @ 30/100 μM)
Caco-2 (A to B, TC7, pH 6.5/7.4)
−4.0/−1.8
−4.4/−3.6
91 × 10−6 cm/s 72 × 10−6 cm/s
d
pharmacokinetic properties
21
22
Intravenous
Cmax (ng/mL)
tmax (min)
t1/2 (min)
AUC0‑∞ (μg/mL·min)
Vd (L/kg)
CLtotal (mL/min/kg)
Oral
max(ng/mL)
tmax (min)
t1/2 (min)
5071
5
17
174
0.35
14
7811
5
119
809
0.53
3.1
C
7757
30
50
732
105
12340
15
355
4388
136
AUC0‑∞ (μg/mL·min)
F (%)
a
b
The maximum concentration of the assay is 200 μM. Determined by
shake-flask method.16 The values given in parentheses were
c
d
determined at Cerep Inc. Determined at Cerep Inc. Data are
mean concentrations in mouse plasma (n = 3) following a single
2.5 mg/kg intravenous dose or 10 mg/kg oral dose.
C
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ACS Medicinal Chemistry Letters
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the rat INS-1E cell line, performed as previously reported,9
where the compound caused significantly increased insulin
secretion (10.75 0.74% of total content with 10 μM 22 vs
8.74
0.54 with vehicle, p < 0.05) at high glucose concen-
tration (12.4 mM) and, as expected, no effect (4.14 0.15% of
total content with 10 μM 22 vs 4.02 0.08 with vehicle) at low
glucose concentration (2.8 mM).
In vivo examination of 22 in an acute intraperitoneal glucose
tolerance test (IPGTT) in normal mice revealed a good dose
dependent response with maximal reduction in glucose level
reached at 50 mg/kg (Figure 1). The study was followed up by
Figure 2. In vivo evaluation of 22 in Sprague−Dawley rats on glucose
tolerance after oral dosing. (A) Effect on plasma glucose levels. (B)
Effect on plasma insulin levels. Means standard errors (n = 6) are
shown (*, p < 0.05; **, p < 0.01; ***, p < 0.001).
The compound demonstrated a potent effect on glucose
tolerance in DIO mice, a situation that was sustained after 29
days of chronic dosing. The compound all together appears as a
promising candidate for development of improved T2D
therapeutics.
ASSOCIATED CONTENT
* Supporting Information
Synthetic procedure, compound characterization, and biological
assays. This material is available free of charge via the Internet
at http://pubs.acs.org.
Figure 1. In vivo evaluation of 22 in mice on glucose tolerance. (A)
Effect of 22 on acute IPGTT in normal mice. Mice were dosed ip with
22, vehicle, or control (sitagliptin, 10 mg/kg). (B) Effect of 22 on
OGTT in a chronic study in DIO mice: acute (4 weeks vehicle prior to
treatment with 22), chronic (4 weeks treatment with 22), and control
(vehicle). Means standard errors (n = 6) are shown (*, p < 0.05;
**, p < 0.01; ***, p < 0.001).
■
S
AUTHOR INFORMATION
Corresponding Author
*(T.U.) E-mail: ulven@sdu.dk.
■
a chronic oral glucose tolerance test (OGTT) study in DIO
mice, which showed that 22 was more effective than 21 (see the
Supporting Information) and that the effect of 22 was fully
sustained after 29 days of daily oral treatment. Additional
evaluation of 22 in rats confirmed a significant glucose lowering
effect for the high doses already after 10 min and for all doses
after 30 min (Figure 2). This was in agreement with an
observed increase in plasma insulin concentration, with
maximum concentration 15 min after glucose challenge. With
an approximately 30-fold higher potency on human than on
rodent receptors, it appears reasonable to expect that the
effective dose would be correspondingly lower in humans.
In conclusion, optimization of the FFA1 alkyne agonists has
resulted in the discovery of 22, a highly potent FFA1 agonist
with excellent physicochemical and pharmacokinetic properties.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Lone Overgaard Storm for excellent technical
assistance and the Danish Council for Independent Research|
Technology and Production (grant 09-070364), the Danish
Council of Strategic Research (grant 11-116196), and the
Canadian Institutes of Health Research (fellowship to B.D.H.)
for financial support.
ABBREVIATIONS
BRET, bioluminescence resonance transfer; FFA1, free fatty
acid receptor 1 (GPR40); IPGTT, intraperetoneal glucose
■
D
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activity of potent and orally available G protein-coupled receptor 40
agonists. J. Med. Chem. 2011, 54, 1365−1378.
tolerance test; LE, ligand efficiency; LLE, ligand lipophilicity
efficiency; OGTT, oral glucose tolerance test
(16) Christiansen, E.; Due-Hansen, M. E.; Urban, C.; Grundmann,
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Kostenis, E.; Kassack, M. U.; Ulven, T. Free fatty acid receptor 1
(FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophi-
licity and improves ADME properties. J. Med. Chem. 2012, 55, 6624−
6628.
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