Discovery of chromane propionic acid analogues as selective agonists of GPR120 with in Vivo activity in rodents

Article abstract of DOI:10.1021/acsmedchemlett.6b00394

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and eva

Full text of DOI:10.1021/acsmedchemlett.6b00394

Letter
pubs.acs.org/acsmedchemlett
Discovery of Chromane Propionic Acid Analogues as Selective
Agonists of GPR120 with in Vivo Activity in Rodents
Gregory L. Adams,*,§ Francisco Velazquez,† Charles Jayne,† Unmesh Shah,†,# Shouwu Miao,†
Eric R. Ashley,† Maria Madeira,† Taro E. Akiyama,† Jerry Di Salvo,† Takao Suzuki,∥ Nengxue Wang,∥
Quang Truong,† Eric Gilbert,† Dan Zhou,† Andreas Verras,† Melissa Kirkland,†,⊥ Michele Pachanski,†
Maryann Powles,† Wu Yin,† Feroze Ujjainwalla,† Srikanth Venkatraman,† and Scott D. Edmondson†
†Merck & Co., Inc., Kenilworth, New Jersey 07033, United States
§Merck & Co., Inc., West Point, Pennsylvania 19486, United States
∥WuXi AppTec, Shanghai 200131, China
S
* Supporting Information
ABSTRACT: GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor
(GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A
selective activator of GPR120 containing a chromane scaffold has been designed,
synthesized, and evaluated in vivo. Results of these efforts suggest that chromane
propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is
selective over the closely related target GPR40 (FFAR1), has a clean off-target profile,
demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/
knockout GPR120 mouse oGTT studies.
KEYWORDS: GPR120, FFAR4, insulin sensitization, type 2 diabetes, chromane
retinopathy, neuropathy, and nephropathy can be encountered
by those afflicted with this disease.5
ype 2 diabetes mellitus (T2DM), a worldwide public
Thealth problem, is a metabolic disorder characterized by
GPR120 (FFAR4) is a long-chain fatty acid sensing G protein-
coupled receptor (GPCR) that is expressed in intestine, lung,
macrophages, and adipose tissue.6,7 Stimulation of this receptor
by free fatty acids has been reported to promote secretion of
glucagon-like peptide-1 (GLP-1).8 Activation has also been
demonstrated to display insulin sensitizing effects in vivo,7 and as
such GPR120 could be an attractive drug target.9,10
Due to the above considerations, a suitable agonist of
GPR120 has been proposed to be desirable as a possible
treatment for type 2 diabetes.11−15 Due to the presence of
multiple free fatty acid receptors that are able to be stimulated
by structurally similar ligands and the manifestation of the
complex pharmacology that can result,16 we counterscreened
against GPR40 (FFAR1) to identify compounds that are
selective for activation of GPR120.17,18 Herein is described our
recent efforts to identify selective and potent agonists of
GPR120 that have suitable pharmacokinetic profiles to support
in vivo studies.
Figure 1. Comparison of core structures.
During the optimization of GPR120 agonists spiropiperidine
1 and benzofuran 2 (Figure 1), which were previously disclosed
by our colleagues,19−22 it was discovered that replacement of
hyperglycemia, pancreatic β-cell impairment, impaired insulin
secretion, and insulin resistance in various tissues, including
skeletal muscle, adipose tissue, and liver.1−3 Inflammation has
been suggested to be a major contributor to this condition,4
and chronic complications such as cardiovascular disease,
Received: October 7, 2016
Accepted: November 21, 2016
© XXXX American Chemical Society
A
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Toward this end, we explored the effects of modifying the
propionic acid side chain via substitution on the carbon chain
and replacement of the acid with various isosteres. Multiple
examples were prepared and tested, but most exhibited a loss of
activity. The most promising derivatives are summarized in
Table 1.
Table 1. SAR Overview of a Promising Series of Chromanes
as GPR120 Agonists
a
Both the R and S chromane enantiomers, 3 and 4, respec-
tively, were found to be agonists of GPR120, but we focused on
the R chromane scaffold for the majority of structure−activity
relationship (SAR) development due to its slightly better in vitro
activity in multiple examples.
Most substitutions on the side chain were found to be
detrimental to activity, but it was discovered that a cyclo-
propionic acid was tolerated and could improve selectivity over
GPR40 as observed in chromane 5. The stereochemical
configuration of the cyclopropane was critical, as the (R,R,R)-
isomer 5 displayed more potency than the (R,S,S)-cyclo-
propane diastereomer 6 for GPR120 activation.
The tetrazole functionality was identified as a possible
carboxylic acid bioisostere, exemplified here by compound 7.
This modification was accompanied by an attenuation of
potency, and the tetrazole 7 seemed to display partial agonist
activity when compared to a standard GPR120 agonist under
the conditions used in the hGPR120 IP1 assay (>50%
activation is considered full).
a
Values are the average of at least two experiments, each in 10-point
titrations. Unless noted, all analogues tested were generally deemed to
be full GPR120 agonists under assay conditions.
Concurrent to the SAR exploration on the acid side chain,
the aryl substitution at the chromane 6-position was also
modified (Table 2). One observed trend was that appropriate
substitution ortho to the fluorine resulted in an improvement
of in vitro potency on GPR120. Furthermore, analogues
containing a trifluoromethoxy group para to the fluorine
were not as selective against GPR40 as analogues where the
the scaffold core with a chromane system, as in propionic acid
3, resulted in maintained agonist activity on GPR120.23
We decided to optimize this chromane series and identify a
selective agonist via an in vitro evaluation using IP1 and
β-Arrestin2 (β-Arr2) assays to measure on target activation of
human (h) GPR120 in conjunction with an IP1 assay to
determine activation of hGPR40.
a
Table 2. Chromane Biaryl SAR Optimization
a
Values are the average of at least two experiments, each in 10-point titrations. Unless noted, all analogues tested were generally deemed to be full
GPR120 agonists under assay conditions.
B
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a
Table 3. Rat IV Pharmacokinetic Data of Selected Chromane
Derived GPR120 Agonists
Table 4. Cyclopropionic Acid Analogues
a
Compound
Clp
t1/2
Vdss
PPB
Clint
3
9.5
5.4
9.1
1.3
3.4
1.6
1.6
1.3
0.64
0.45
0.23
0.24
0.49
0.14
0.15
99.84
99.93
99.77
99.76
99.68
99.97
99.93
10500
8700
4500
560
11
16
18
19
20
21
1.3
0.74
2.1
2.4
760
0.93
1.2
6200
3600
a
Clp, plasma clearance (mL/min/kg); t1/2, terminal half-life (h); Vdss,
volume of distribution at steady state (L/kg); PPB, plasma protein
binding (% bound extrapolated from 10% plasma); Clint, intrinsic
clearance (mL/min/kg). IV cassette dosing (DMSO/PEG400/H2O =
20/60/20; 0.1 mg/kg).
substituent was replaced with a cyclobutoxy group. Replace-
ment of the phenyl ring with a series of pyridine analogues was
evaluated, and the 6-cyclobutoxy-3-fluoropyridin-2-yl derivative
16 displayed better potency on GPR120 than fluoro pyridines
14 or 15. Similar to the SAR observed when employing a
phenyl ring, substitution ortho to the fluorine in the methoxy
pyridine analogue 17 improved potency on GPR120.
Further exploration of substitution on the cyclobutyl ring
revealed that trans-methoxy substitution at the 3-position was
tolerated in analogues 18 and 19. Aryl groups could also be
used to replace the cyclobutyl ring with retention of potency,
exemplified here by the methyl thiazoles 20 and 21.
a
Values are the average of at least two experiments, each in 10-point
titrations. Unless noted, all analogues tested were generally deemed to
be full GPR120 agonists under assay conditions.
a
Table 5. Tetrazole Analogues
Upon identification of these potent and selective com-
pounds, promising derivatives were studied to determine their
pharmacokinetic (PK) profiles in rats via IV dosing (Table 3).
Oral bioavailability was >70% for compounds throughout this
series (vide infra, Table 7), so optimization of rat half-life
through lowering intrinsic clearance was a main factor that
guided SAR development and tool compound selection. All
compounds were >99% bound to plasma proteins. Analysis of
intrinsic clearance (Clint) for this series suggested that
chromanes 18 and 19 may be good choices as potential tool
compound candidates due to their comparatively low Clint and
longer half-lives in rats. Consequently, these compounds were
selected for further in vivo evaluation.
Promising propionic acid replacements were next evaluated
in combination with the optimized aryl groups from Table 2.
SAR trends were maintained in the case of the cyclopropane
containing analogues (Table 4); substitution ortho to the
fluorine improved activity, and trans-methoxy substitution was
tolerated.
Congeners combining the best aryl groups and a replacement
of the carboxylic acid with the tetrazole moiety were also
synthesized and evaluated (Table 5). In the case of the tetrazole
series, methoxy substituion ortho to the fluorine provided a
more marked improvement in potency on GPR120 than did
the difluoro substitution. The analogues with weaker potency
seemed to display partial activity on hGPR120 under the
conditions of the IP1 assay. This partial activity was not
observed in the β-Arr2 assay, however, and upon identifying
analogues with improved potency this partial behavior returned
to full agonism. Importantly, compound 26, which displayed
similar potency and full agonist activity in a mouse GPR120 IP1
assay (results not shown), demonstrated in vivo efficacy in a
mouse oral glucose tolerance test (oGTT) (Figure 2). These
results suggest that exploration of the tetrazole series or other
a
Values are the average of at least two experiments, each in 10-point
titrations. Unless noted, all analogues tested were generally deemed to
be full GPR120 agonists under assay conditions.
carboxylic acid bioisosteres could potentially be an area for
future investigation.
We evaluated compounds 18, 24, and 26 in vivo using the
mouse oral glucose tolerance test (oGTT).24 Figure 2 sum-
marizes the results of compounds 18 (3, 10, 30 mg/kg) in a
dose titration and single dose evaluation of 24 (30 mg/kg) and
C
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Figure 2. Glucose lowering effects as measured by mouse oGTT. The
following doses were used, resulting in the corresponding plasma
concentrations (Cp) at 3 h: 18, 3 mg/kg [n = 3, 0.75 μM (s =
0.04 μM)]; 10 mg/kg [n = 3, 1.17 μM (s = 0.13 μM)]; 30 mg/kg [n = 3,
3.12 μM (s = 1.02 μM); 24, 30 mg/kg [n = 3, 37.4 μM (s = 3.43 μM)];
26, 100 mg/kg [n = 3, 40.6 μM (s = 16.4 μM)]. (A) Blood glucose
(mg/dL) over time (minutes). (B) Net blood glucose area under
the curve (AUC). Vehicle (veh); dextrose (dex) challenge; Tx =
vehicle and compound administration; mpk = mg/kg. **P < 0.01
compared to vehicle, ***P < 0.0001 compared to vehicle; two-way
ANOVA.
26 (100 mg/kg). All three compounds showed reduction of
blood glucose, demonstrating that propionic acid replacements
such as the cyclopropionic acid and the tetrazole are capable of
exhibiting in vivo glucose lowering activity. Further-
more, compound 18 showed a dose-dependent glucose
reduction with a plateau of efficacy observed at 10 mg/kg
thus defining the minimum dose that afforded maximal efficacy
(MEDmax) in this model.
In a further set of wild-type/GPR120 knockout mouse
oGTT experiments, compounds 18 and 19 both displayed
glucose lowering at the superpharmacologic dose of 150 mg/kg
in wild-type mice (Figure 3). Meanwhile, no efficacy was
observed in the GPR120 knockout mice, suggesting that
glucose lowering observed at very high doses is still linked to
GPR120 activation. The in vitro profile of compounds 18 and
19 on mouse (m) GPR120 and mGPR40 was similar to that
observed for the human receptor (Table 6).
Compound 18 was evaluated for potency in common off-
target in vitro assays. Ion channel activity was determined to be
minimal (IC50s at Cav1.2 = 28 μM,25 IKr > 60 μM,26 Nav1.5 =
27 μM27), and the cytochrome P-450 inhibition was also
negligible (CYP3A4, CYP2D6, CYP2C9 IC50s > 50 μM).28
Additionally, compound 18 was characterized in a general
broad panel screen of enzyme, ion channel, and GPCR assays
Figure 3. (A,B) Mouse oGTT of compound 18 in wild-type [150 mg/
kg; n = 4, 3 h Cp= 43.9 μM (s = 15.8 μM)] and GPR120 knockout
[150 mg/kg; n = 4, 3 h Cp = 53.4 μM (s = 14.0 μM)] mice. (C,D)
Mouse oGTT of compound 19 in wild-type [150 mg/kg; n = 4, 3 h Cp
= 33.5 μM (s = 21.0 μM)] and GPR120 knockout [150 mg/kg; n = 4,
3 h Cp = 27.6 μM (s = 6.03 μM)] mice. (A,C) Blood glucose (mg/dl)
over time (minutes). (B,D) Net blood glucose area under the curve
(AUC). Vehicle (veh); dextrose (dex) challenge; Tx = vehicle and
compound administration; mpk = mg/kg. **P < 0.01 compared to
vehicle, two-way ANOVA.
D
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a
Table 6. Mouse in Vitro Data for Compounds 18 and 19
AUTHOR INFORMATION
Corresponding Author
*Phone: (215) 652-1232. E-mail: gregory.adams2@merck.com.
ORCID
Gregory L. Adams: 0000-0002-3452-7439
Eric R. Ashley: 0000-0002-0513-3342
■
mGPR120 EC50 (nM)
Compound
IP1
β-Arr2
mGPR40 IP1 EC50 (nM)
18
19
6.4
5.6
6.8
4.6
>10k
>10k
a
Values are the average of at least two experiments, each in 10-point
Present Addresses
titrations. Unless noted, all analogues tested were generally deemed to
be full GPR120 agonists under assay conditions.
#(U.S.) Jones Day, 250 Vesey Street, New York, NY 10281,
USA.
⊥(M.K.) Charles River Laboratories, 334 South St., Shrewsbury,
MA 01545, USA.
Table 7. Pharmacokinetic Profile of Compound 18 Across
Multiple Species
a
Notes
property
rat
mouse
Rhesus
The authors declare no competing financial interest.
AUCIV (μM·h)
Clp (mL/min/kg)
Vdss (L/kg)
35.9
1.1
8.1
9.9
57.8
0.33
0.27
9.8
ACKNOWLEDGMENTS
■
0.3
1.4
The authors would like to acknowledge the following people
whose efforts enabled the absolute stereochemical assignments
for the compounds in this manuscript (see SI): Scott Borges
(SFC); Leo A. Joyce, Edward Sherer, and Joe Shpungin
(Vibrational Circular Dichroism (VCD) spectroscopy); and
Alexei Buevich (NMR).
t1/2 (h)
4.6
3.0
MRT (h)
4.6
2.4
13.5
82
Foral (%)
93
76
PPB (% bound)
Clint (mL/min/kg)
99.76
470
99.67
3400
99.78
150
a
AUCiv, area under the plasma concentration vs time curve following
IV dosing; Clp, plasma clearance; Vdss, volume of distribution at
steady state; t1/2, terminal half-life; MRT, mean residence time; Foral
ABBREVIATIONS
■
,
FFAR1, free fatty acid receptor 1; FFAR4, free fatty acid
receptor 4; T2DM, type 2 diabetes mellitus; GLP-1, glucagon
like peptide 1; GPR120, G-protein coupled receptor 120;
GPCR, G-protein coupled receptor; GPR40, G-protein coupled
receptor 40; IP1, D-myo-inositol-1-phosphate; oGTT, oral
glucose tolerance test
oral bioavailability; PPB, plasma protein binding; Clint, intrinsic
clearance. IV dosing in DMSO/PEG400/H2O = 20/60/20 (rat
1 mg/kg, mouse 2 mg/kg, Rhesus 0.5 mpk). PO dosing via suspension
in methylcellulose 0.5% (rat 2 mg/kg, mouse 30 mg/kg, Rhesus
1 mpk).
and displayed minimal activity, including at PPAR alpha, delta,
and gamma (>10 μM).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.6b00394.
■
S
Experimental procedures and analytical data for the
synthesis of all compounds; GPR120 and GPR40 in vitro
assay procedures; PK protocol; oGTT protocols (PDF)
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