Design, synthesis and SAR of a novel series of heterocyclic phenylpropanoic acids as GPR120 agonists

Article abstract of DOI:10.1016/j.bmcl.2017.06.028

A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.

Full text of DOI:10.1016/j.bmcl.2017.06.028

Accepted Manuscript
Design, Synthesis and SAR of a Novel Series of Heterocyclic Phenylpropanoic
Acids as GPR120 Agonists
Xuqing Zhang, Chaozhong Cai, Michael Winters, Michele Wells, Mark Wall,
James Lanter, Zhihua Sui, Jingyuan Ma, Aaron Novack, Imad Nashashibi,
Yuanping Wang, Wen Yan, Arthur Suckow, Hong Hua, Austin Bell, Peter Haug,
Wilma Clapper, Celia Jenkinson, Joseph Gunnet, James Leonard, William V.
Murray
PII:
S0960-894X(17)30631-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.06.028
BMCL 25062
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 April 2017
8 June 2017
9 June 2017
Please cite this article as: Zhang, X., Cai, C., Winters, M., Wells, M., Wall, M., Lanter, J., Sui, Z., Ma, J., Novack,
A., Nashashibi, I., Wang, Y., Yan, W., Suckow, A., Hua, H., Bell, A., Haug, P., Clapper, W., Jenkinson, C., Gunnet,
J., Leonard, J., Murray, W.V., Design, Synthesis and SAR of a Novel Series of Heterocyclic Phenylpropanoic Acids
as GPR120 Agonists, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2017.06.028
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Design, Synthesis and SAR of a Novel Series of
Heterocyclic Phenylpropanoic Acids as
GPR120 Agonists
Leave this area blank for abstract info.
Xuqing Zhanga,*, Chaozhong Caia, Michael Wintersa, Michele Wellsa, Mark Walla, James Lantera, Zhihua Suia,
Jingyuan Mab, Aaron Novackb, Imad Nashashibib, Yuanping Wanga, Wen Yana, Arthur Suckowa, Hong Huaa,
Austin Bella, Peter Hauga, Wilma Clappera, Celia Jenkinsona, Joseph Gunneta, James Leonarda and William V.
Murraya
aCardiovascular and Metabolic Research, Janssen Research & Development, LLC, Welsh & McKean Roads, Box 776, Spring House, PA 19477
bCymaBay Therapeutics, Inc., 7999 Gateway Blvd, Newark, CA 94560
A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives (I) was discovered as
potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.
R1
R3
H
O
O
R2
OH
I
H
: 5-membered heteroaryl
1

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Design, Synthesis and SAR of a Novel Series of Heterocyclic Phenylpropanoic Acids
as GPR120 Agonists
Xuqing Zhanga,*, Chaozhong Caia, Michael Wintersa, Michele Wellsa, Mark Walla, James Lantera, Zhihua Suia,
Jingyuan Mab, Aaron Novackb, Imad Nashashibib, Yuanping Wanga, Wen Yana, Arthur Suckowa, Hong Huaa, Austin
Bella, Peter Hauga, Wilma Clappera, Celia Jenkinsona, Joseph Gunneta, James Leonarda and William V. Murraya
aCardiovascular and Metabolic Research, Janssen Research & Development, LLC, Welsh & McKean Roads, Box 776, Spring House, PA 19477
bCymaBay Therapeutics, Inc., 7999 Gateway Blvd, Newark, CA 94560
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel series of 5-membered heterocycle-containing phenylpropanoic
acid derivatives was discovered as potent GPR120 agonists with low
clearance, high oral bioavailability and in vivo antidiabetic activity in
rodents.
Received in revised form
Accepted
Available online
Keywords:
2017 Elsevier Ltd. All rights reserved.
GPR120
Type 2 diabetes
Phenylpropanoic acid
GPR120 is a Gq coupled GPCR activated by long-chain fatty
acids (LCFAs). It is expressed in intestine, lung, adipose tissue,
potent GPR120 agonistic activity and good physical properties.
Furthermore, the PK profiles of the lead compounds were
suitable for further development, with low clearance and high
oral bioavailability in rodents.
and pro-inflammatory macrophages.
Upon stimulation by
LCFAs, GPR120 has been implicated in GLP-1 secretion, insulin
sensitization, anti-inflammation, and appetite control.1-3
Therefore, GPR120 has emerged as an attractive target for the
treatment of metabolic and inflammatory diseases such as obesity
and type 2 diabetes.4
Compounds were screened in a calcium flux assay with
human GPR120 transfected HEK293 cells15 and in a β-arrestin
assay with a PathHunter CHO-K1 cell line expressing human
GPR120.16 We began our SAR exploration with ortho-biphenyl
containing compound (IIb) as the starting point (Table 1).
Consistent with the data for IIa in the literature, the close
analogue IIb displayed good hGPR120 potency in the calcium
flux assay (EC50 of 220 nM). Then we replaced the core phenyl
group with various 5-membered heteroaryl groups (B-ring). The
5-membered heteroaryl groups that we investigated included
pyrrole (4a) and (4b), imidazole (4c), pyrazole (8a) and (8b),
triazole (12), tetrazole (16), thiophene (20a) and (20b), thiazole
(20c), isothiazole (20d and 20e), oxazole (20f), and isoxazole
(25a, 25b and 29). A preliminary SAR study of the R1 substituent
of the left side terminal phenyl ring (A ring) revealed that optimal
potency could be achieved by introduction of a Cl group or a Et
group at the 4-position (data not shown). Hence, a diverse
selection of 5-membered heteroaryl substituted phenylpropanoic
acids bearing the optimal R1 group were synthesized and the
compounds were screened in the GPR120 in vitro assays.
There are only a few reports of GPR120 agonists in the
literature.5-13 Further research is needed to discover potent,
selective and orally bioavailable small molecule GPR120
agonists. Recently Milligan and co-workers reported a series of
phenylpropanoic acid derivatives containing a biphenyl motif as
GPR120 agonists by screening representative GPR40 ligands
against GPR120.14 Optimization led to a potent and selective
GPR120 agonist (IIa) with an EC50 value of 44 nM against
human GPR120 (hGPR120) (Figure 1).
SAR studies
demonstrated that the 1,2-relationship of the [1,1'-biphenyl]-2-yl-
methoxyphenyl (ortho-biphenyl) core of the scaffold was
essential for hGPR120 activity and selectivity over hGPR40.
Compound IIa is relatively hydrophobic. Therefore we sought
ways to modify the structure to improve pharmaceutical
properties, while retaining or improving oral bioavailability and
GPR120 potency. Our strategy to accomplish this goal was to
replace the fluoro-phenyl group of (IIa) with a 5-membered
heteroaryl group, which should improve pharmaceutical
properties by increasing polarity (Figure 1).
We describe herein our exploration of the design, synthesis,
and SAR of a novel series of 5-membered heterocycle-containing
phenylpropanoic acid derivatives (I) as GPR120 agonists.
Optimization of this series generated several lead scaffolds with
____________________________________________________
*Corresponding
author.
Telephone:
+1-215-628-7877;
e-mail:
Figure 1. Design of 5-membered heteroaryl phenylpropanoic acids
xzhang5@its.jnj.com
2

Table 1. SAR of Five Membered Cores, R1 and R2
hGPR120 CaMb
EC50 (nM)
hGPR120 β-arrestinc
EC50 (nM)
ID
R1
cLogPa
IIb
4-Cl
6.79
220
ntd
4a
4b
4-Cl
4-Et
6.41
6.67
145
100
930
750
4c
4-Cl
5.15
>5,000
nt
8a
8b
4-Cl
4-Et
5.34
5.57
610
520
2,030
1,150
12
4-Cl
4-Cl
4-Et
4-Et
4-Cl
4.92
3.93
6.75
6.75
5.35
>5,000
>5,000
142
nt
nt
O
N
N
N
N
16
20a
20b
20c
711
900
nt
O
160
S
81
20d
20e
4-Cl
4-Et
5.74
6.03
217
190
1,342
nt
20f
4-Cl
4-Cl
4.69
5.01
1,750
1,440
nt
25a
2,760
25b
29
4-Cl
4-Cl
5.23
5.23
270
350
760
810
a cLogP was calculated by ChemBioDraw 14.0;b Calcium flux assay in human GPR120 transfected HEK293 cells; c β-arrestin assay in human GPR120
expressing PathHunter CHO-K1 cells; c nt: not tested
Replacement of the phenyl group of IIb (B ring, cLogP = CaM 100 nM and EC50 β–arrestin 750 nM) than 4a. Attempts to
6.79) with a slightly more polar pyrrolyl group (cLogP = 6.41) significantly increase polarity (cLogP = 5.15) by introduction of
was well tolerated, as evidenced by compound 4a with EC50 an imidazole ring (4c) abolished hGPR120 activity. Replacing
values of 145 nM in the calcium flux assay and 930 nM in the β- the imidazole ring with a less polar pyrazole ring slightly
arrestin assay. It was noted that the analogue with the 4-Et increased cLogP value to 5.34 but significantly improved
substituted phenyl group (4b) was slightly more potent (EC50 hGPR120 potency (8a, EC50 CaM 610 nM and 8b, EC50 CaM
3

520 nM). Consistent with these results, introduction of the polar thiazole and isothiazole were examined. To our delight,
triazole (12, cLogP = 4.92) and tetrazole cores (16, cLogP = compounds bearing those lipophilic cores (20a-20e) had EC50
3.93) were detrimental to hGPR120 activity, highlighting the values in the calcium flux assay that were in the range from 81 to
importance of the lipophilicity of the B-ring. Hence, more 217 nM, reaching the primary goal upon optimization.
lipophilic 5-membered heteroaryl rings such as thiophene,
Table 2. SAR of R1-R4 substituents of the isoxazole-containing phenylpropanoic acids
Microsomal Stability
(% remaining at 10 min)
PPBd
(%)
hGPR120 CaMa
EC50 (nM)
hGPR120 β-arrestinb
EC50 (nM)
ID
R1
R2
R3
R4
human
mouse
rat
human
mouse
rat
25a
25b
25c
25d
25e
25f
4-Cl
4-Cl
H
Me
2,3-di-Me
2,3-di-Me
2,3-di-Me
2,3-di-Me
2,3-di-Me
2,3-di-Me
2,3-di-Me
2,3-di-F
3,5-di-F
-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
1,440
270
740
1,060
1,070
2,830
680
670
71
ntc
760
400
130
1,090
nt
4-Cl
4-Cl
Et
66.3
79.3
50.2
48.3
45.6
38.4
n-Pr
cyclo-Pr
Ph
4-Cl
4-Cl
25g
25h
25i
4-Cl
4-Cl
4-Cl
4-Cl
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
160
140
160
nt
80.9
99.6
113.0
91.2
109.1
105.0
68.0
105.5
98.9
99.93
99.83
99.86
99.53
99.81
98.78
25j
150
410
1,450
170
150
120
71
25k
25l
4-Cl
4-Cl
2-Me,5-F
2-CF3
nt
nt
69
25m
25n
25o
25p
25q
25r
25s
25t
-
4-F
4-Br
3,5-di-F
3,5-di-F
3,5-di-F
3,5-di-F
3,5-di-F
3,5-di-F
3,5-di-F
3,5-di-F
3,5-di-F
3,5-di-F
95.6
102.7
104.7
108.1
64.4
93.0
119.4
94.1
99.3
84.5
110.2
66.2
72.3
92.0
37.9
230
nt
2-Cl-4-F
4-Me
4-Et
4-cyclopropyl
4-CF3
4-OMe
4-Me
290
180
60
120
57
170
340
1,130
99.94
99.92
99.89
nt
190
nt
160
25u
25v
110
b
93.0
86.3
54.3
a Calcium flux assay in human GPR120 transfected HEK293 cells; β-arrestin assay in human GPR120 expressing PathHunter CHO-K1 cells; cnt: not tested; d
PPB: plasma protein bining
Compounds 20d and 20e were particularly interesting as they
exhibited comparable hGPR120 potency as IIa (EC50 CaM 217
nM for 20d and 190 nM for 20e) despite containing the relatively
more polar isothiazole core. Unfortunately, 20d and 20e
displayed only moderate microsomal stability (85.9% and 75.2%
remaining at 10 min in human liver microsomes, 73.4 % and
75.5% remaining at 10 min in mouse liver microsomes,
respectively),17 which suggested that optimization of metabolic
stability was required among this series of compounds.
Compounds 20f (cLogP = 4.69) and 25a (cLogP = 5.01) bearing
the more polar oxazole and isoxazole cores, respectively,
displayed weaker hGPR120 potency (20f, EC50 CaM 1,750 nM;
25a, EC50 CaM 1,440 nM) relative to the isothiazole containing
analogues. In light of these results, we attempted to introduce a
slightly more lipophilic isoxazole core into the scaffold in an
effort to further improve hGPR120 potency. Substitution of a
methyl group at either 2 or 5-position of the isoxazole ring
slightly increased cLogP value to 5.23 compared to 25a, but
resulted in satisfactory improvement in hGRP120 potency (EC50
CaM 270 nM for 25b and 350 nM for 29), which provided a
good starting point for further development. Overall, through the
B-ring SAR, the isoxazole containing phenylpropanoic acids
could maintain comparable hGPR120 potency with reduced
cLogP values to the phenyl substituted analogue IIb.
Encouraged by the good hGRP120 potency of the isoxzole-
containing phenylpropanoic acid derivative (25b), a detailed
SAR study of the R1-R4 substituents was conducted (Table 2).
Substitution in the 5-position of the isoxazole ring with a small
alkyl group such as methyl or ethyl provided a 2- to 6-fold
increase in hGPR120 potency in the calcium flux assay compared
with the R2 unsubstituted isoxazole analogue (EC50 CaM of 270
nM for 25b and 740 nM for 25c vs. 1,440 nM for 25a). However,
bulkier alkyl groups such as n-propyl or cyclopropyl as well as
phenyl groups (25d-f) were not well tolerated. Compounds 25c
and 25d displayed moderate microsomal stability across three
species. In an attempt to improve metabolic stability of the
scaffold, a trifluoromethyl group (CF3) was introduced at the 5-
position of the isoxazole ring (25g), which resulted in a slight
drop on hGPR120 potency compared to the methyl analogue 25b
(EC50 680 nM for 25g). Given the good in vitro metabolic
stability profile of 25g (80.9% remaining at 10 min in human
liver microsomes, 91.2% remaining at 10 min in mouse liver
microsomes and 68.0% remaining at 10 min in rat liver
microsome), the 5-CF3 substituted isoxazole containing
phenylpropanoic acid scaffold was selected for further SAR
studies of the R1, R3 and R4 substituents. In general, a halogen (F
or Cl or Br) or a small alkyl group (Me, Et and cyclopropyl) was
the preferred R1 substituent (25g-k, 25n-s), albeit the A-ring
unsubstituted analogue was equally potent (25m). Compound
4

Scheme 1. Reagents and conditions: a) Cu(OAc)2, 4-R1-Ph-B(OH)2 (R1 = Cl, Et), MeOH, r.t. to 60oC overnight (77~95%); b) DIBAL r.t. in THF, 1 h (75~88%);
c) ADDP, Bu3P, 4-OH-R3-PhCH2CH2CO2H (R3 = 2,3-di-Me), in toluene, r.t. to reflux 2 h (50~72%); d) LiOH in H2O/THF/MeOH, r.t. 2 h (70~95%); e) 1,1-
dimethoxy-N,N-dimethylmethanamine 2 h followed by (4-R1-phenyl)hydrazine (R1=Cl, Et) in refluxing toluene overnight (50-72%); f) Cu2O, 1,10-
phenanthroline,110oC (82-91%); g) HBr, r.t 2 h (71-75%); h) Cs2CO3, 4-OH-2,3-di-Me-PhCH2CH2CO2H DMF, r.t (70-75%); i) Cs2CO3, 3-chloroprop-1-yne in
DMF r,t. 6 h (80%); j) 4-Cl-PhN3, DMF 80oC for 6 h, (53%); k) CCl4, PPh3 in DCM, 0oC~r.t, 2h (45%); l) NaN3, TEA, DMF, r.t. to 80oC 2h, (65%); m) Tf2O,
TEA, DCM, -78oC to r.t., 2 h (80%); n) Pd(PPh3)4, Na2CO3, DME, 4-R1-Ph-B(OH)2 (R1 = Cl, Et), 80-120oC, 2~6 h, (65~88%); o) NaBH4 0oC to r.t. 10 min
(85%)
Scheme 2. Reagents and conditions: a) NH2OH in MeOH, r.t. to 60oC, 4 h (80~92%); b) NCS in DCM, 0oC for 2 h (77~82%); c)
(R2 = Me, Et, n-
Pr, cyclo-Pr, Ph), TEA in DCM 0oC for 2 h (45~66%); d) propargyl alcohol, chloro(1,5-cyclooctadiene)(pentamethylcyclopentadienyl)Ru(II) in DCM r.t.
overnight (50%); e) 2 N NaOH, THF/H2O, r.t to 50oC 2 h (82~88%); f) BH3/THF complex, 0oC to r.t, 2 h (45~70%); g) ADDP, Bu3P, 4-OH-R3-
PhCH2CH(R4)CO2Et (R3 = 2,3-di-Me, 2,3-di-F, 3,5-di-F, 2-CF3, 2-Me,5-F; R4 = H, Me), in toluene, r.t. to reflux 2 h (52~75%); h) LiOH in H2O/THF/MeOH, r.t.
2 h (66~87%); i) ethyl 5,5,5-trifluoro-2,4-dioxopentanoate, TEA in DCM r.t overnight (75~77%); j) ethyl 3-oxobutanoate, MgCl2, pyridine, r.t. overnight (70%)
5

25p with halogen substituents at the 2 and 4 positions of the A-
ring also exhibited good hGPR120 potency (EC50 CaM 71 nM).
Surprisingly, the introduction of a trifluoromethyl substituent at
the 4-position (25t, EC50 CaM 340 nM) led to a >2 fold drop in
hGPR120 potency compared with the methyl analogue 25q (EC50
CaM 120 nM) probably due to an electronic effect. Addition of a
polar, electron-donating substituent such as methoxy at the 4-
position resulted in a significant drop in hGPR120 potency (EC50
CaM 1.13 µM for 25u). We then examined the effect of a limited
group of the R3 substituents on hGPR120 potency within the 5-
CF3 substituted isoxazole containing phenylpropanoic acid
subseries. The 2,3-di-Me or 2-Me-5-F substituent pattern at the
R3 position had been considered an effective modification to
hinder β–oxidation of the propanoic acid side chain.18 We
hypothesized that a 2,3-di-F, a 3,5-di-F, or a 2-CF3 substituent at
the R3 position could reduce the electron density and block
oxidation of the phenyl ring and the propanoic acid side chain.
We were gratified to find that both types of modifications led to
analogues with good hGPR120 potency (with the exception of
2-CF3 as in 25l) and improved microsomal stability with the 3,5-
di-F substitution at the R3 position preferred. In particular, 25i
and 25m-p exhibited excellent hGPR120 potency (EC50 CaM
71~170 nM) and superior metabolic stability in liver microsomal
preparations (95~>100% remaining at 10 min in human and
93~>100% in mouse liver microsomes). Introduction of an α–
methyl group on the propanoic acid side chain at the R4 position
was also tolerated, as illustrated by 25v with equal potency (EC50
CaM 110 nM) to the R4 unsubstituted analogue 25q.
Furthermore, 25v boosted human liver microsomal stability from
64% to 93% remaining at 10 min compared to 25q. This
modification could provide another effective tool to block β–
oxidation of the propanoic acid side chain leading to improved
metabolic stability.
Table 3. Full PK Profiles ofSelected Compounds in the Micea
b
c
c
ID
CLb
mL/min/kg
7.18
Vss
T1/2
(h)
Cmax
AUCc
h*ng/mL
43152
78612
9661
F
L/kg
1.26
0.336
0.898
ng/mL
12667
16150
7673
(%)
93.0
49.5
78.7
25i
25m
25r
2.07
2.58
1.03
2.09
27.1
a C57/black 6J mice; b IV parameters, 5 mg/kg in 20% HPBCD (n=3); c PO parameters,
20 mg/kg in 0.5% methocel (n=3)
Figure 2. Compound 25i and 25r reduced AUC of blood glucose
in C57 BL/6J mice (IPGTT): Dunnet’s Analysis (P<0.05 = *,
P<0.01 = **, P<0.001 = *** vs Vehicle)
Given their promising in vitro profiles, selected compounds
from the 5-CF3 substituted isoxzole-containing phenylpropanoic
acid subseries (25) were evaluated in a mouse pharmacokinetic
study at an oral dose of 20 mg/kg in 0.5% methocel and at an iv
dose of 5 mg/kg in 20% HPβCD (Table 3).19 All three selected
compounds (25i, 25m and 25r) displayed high plasma protein
binding across species due to their fatty acid feature (Table 2).
Consistent with in vitro data on microsomal stability, 25i
(R1=Cl) and 25m (R1 =H) demonstrated excellent exposure in
plasma after oral dosing (AUClast = 43152 and 78612 h*ng/mL).
Both compounds had very low clearance (7.18 and 2.09 mL/min
kg) and a volume of distribution at steady state (Vss = 1.26 and
0.336 L/kg) within our target range. In comparison, 25r (R1=Et)
displayed faster clearance (27.1 mL/min/kg) and moderate oral
exposure (AUC h*ng/mL 9661) in mice, which was also
consistent with the in vitro microsomal stability data for the
methyl analogue 25q (R1=Me), suggesting that an alkyl group at
the 4-position of the phenyl ring might be a metabolic liability.
An intraperitoneal glucose tolerance test (IPGTT) was utilized
to assess the in vivo antidiabetic properties of GPR120 agonists
25i and 25r in C57BL/6J mice (Figure 2). Thus, the effect was
investigated by oral dosing at 1 mg/kg, 3 mg/kg and 10 mg/kg 30
min prior to an intraperitoneal glucose challenge at a dose
volume of 1.5 g/kg. Compound 25r showed a dose response for
lowering glucose in the first 30 minutes post compound
administration and for overall lowering of glucose delta AUC
(area under the curve). Compound 25i at 10 mg/kg reduced
plasma glucose levels with delta AUC of 56% (p<0.001) after
120 min when compared with glucose alone.
6

The general synthetic routes to the 5-membered heterocycle-
containing phenylpropanoic acid derivatives are shown in
Schemes 1 and 2. Pyrrole or imidazole 1 was coupled with
commercially available phenylboronic acid under Cu(II) catalysis
to afford the corresponding arylpyrrole or arylimidazole 2a, 2b or
2c in 77~95% yield.21 Esters 2 were reduced by DIBAL to give
the corresponding alcohols 3 in 75~88% yield. Alcohols 3 were
then coupled with substituted ethyl 3-(4-hydroxyphenyl)-
propanoates under modified Mitsunobu condition (ADDP and
Bu3P) in toluene followed by hydrolysis of the
phenylpropanoates with LiOH to afford the phenylpropanoic
acids 4a-4c in good yields.22 Methyl 4-methoxy-3-oxobutanoate
5 was treated with 1,1-dimethoxy-N,N-dimethylmethanamine
followed by condensation with 4-chloro or 4-ethyl
phenylhydrazine hydrochloride in refluxing toluene to give the
corresponding pyrazoles 6 in 50-72% yield. Esters 6 were
hydrolyzed to the corresponding acids under basic conditions
which then underwent decarboxylation with Cu(II) oxide in 1,10-
phenanthroline. Conversion of the benzyl methoxides to the
benzyl bromides 7 were accomplished by treatment with HBr.
Benzyl bromides 7 were coupled with ethyl 3-(2,3-dimethyl-4-
hydroxyphenyl)propanoate in the presence of Cs2CO3 followed
by hydrolysis of the esters to afford the pyrazole containing
phenylpropanoic acid 8a and 8b. 3-(2,3-Dimethyl-4-
hydroxyphenyl)propanoate 9 was reacted with 3-chloroprop-1-
yne in the presence of Cs2CO3 in DMF to give alkyne 10 in 80%
yield, which underwent 1,3-dipolar cycloaddition with 4-Cl-PhN3
to afford triazole 11 in 53% yield. After hydrolysis of the ester,
the triazole containing phenylpropanoic acid 12 was obtained in
good yield. Ethyl 2-((4-chlorophenyl)amino)-2-oxo-acetate (13)
was chlorinated by treatment with CCl4 and Ph3P followed by
intermolecular 1,3-dipolar cyclization with NaN3 to afford the
tetrazole ester 14 in 29% yield.23 The ester was reduced with
DIBAL (15), coupled with ethyl 3-(2,3-dimethyl-4-
hydroxyphenyl)propanoate, and the corresponding ester was
hydrolyzed to yield the tetrazole containing phenylpropanoic
acid 16. Compounds 17 were either commercially available or
prepared by triflation of the phenols with triflic anhydride and
triethyl amine. Suzuki couplings of 17 and various phenylboronic
acids by treatment with Pd(PPh3)4 and Na2CO3 afforded the
corresponding arylated adducts 18 in 65~88% yield, which were
then reduced by either DIBAL for the esters or NaBH4 for the
aldehydes to give alcohols 19. Coupling alcohols 19 with ethyl 3-
(2,3-dimethyl-4-hydroxyphenyl)propanoate under modified
Mitsunobu conditions followed by LiOH hydrolysis afforded the
phenyl-5-(trifluoromethyl) isoxazole-4-carboxylates 23a
in
75~77% yield.26 Compounds 23a were converted to alcohols 24a
by hydrolysis and BH3 reduction. Coupling of alcohols 24a with
various 3-(4-hydroxyphenyl) propanoates followed by hydrolysis
afforded 5-CF3 substituted isoxazole containing phenylpropanoic
acids 25g-v.
Acylation of ethyl 3-oxobutanoate with 4-
chlorobenzoyl chloride (26) in the presence of MgCl2 in pyridine
produced ethyl 2-(4-chlorobenzoyl)-3-oxobutanoate 27 in 70%
yield. Compound 27 was condensed with hydroxylamine to form
ethyl
5-(4-chlorophenyl)-3-methylisoxazole-4-carboxylate,27
which was then hydrolyzed and reduced to alcohol 28. Coupling
28 with 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed
by hydrolysis afforded 3-methyl substituted isoxazole containing
phenylpropanoic acid 29.
In summary, a lead generation process has been conducted for
identifying a novel series of 5-membered heterocycle-containing
phenylpropanoic acids as potent GPR120 agonists. By optimizing
GPR120 potency in calcium flux and β-arrestin assays, several 5-
membered heteroaryl groups were shown to be effective B-ring
replacements for the phenyl group to yield compounds with
nanomolar
GPR120
agonistic
activity.
Furthermore,
representative compounds demonstrated excellent PK profiles,
with low clearance, high oral exposure and acceptable half-life.
The lead compound 25i and 25r demonstrated in vivo antidiabetic
activity in C57BL/6J mice. It is expected that more lead
compounds from this series be further explored in disease related
chronic studies to exploit the therapeutic potential of GPR120
agonists for inflammation and metabolic diseases.
Acknowledgments
The authors thank the ADME/PK team at Janssen R&D for
their technical assistance. The authors gratefully acknowledge
Dr. Mark Macielag for scientific discussion and revising the
paper.
References and notes
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7

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dosing of treatments. An Ascensia BREEZE Blood Glucose
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immediately after. All groups were dosed 30 minutes prior to
glucose administration at a dose volume of 10 mL/kg (the dose
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splice variant of the GPR120 receptor. The assay platform utilizes
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Ca+2 sensitive dye, Fluo-4 NW. Upon stimulation, intracellular
released Ca+2 can bind to the dye and alter its fluorescence
intensity. This increase in fluorescence signal, and thus the flux in
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imaging using a FLIPR reader. The effect of the agonist is
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ProLink/Enzyme Donor (PK)-tagged GPCR and the Enzyme
Activator (EA)-tagged β-arrestin fusion proteins. Upon GPR120
receptor stimulation / activation, the EA-tagged β-arrestin portion
is translocated to the tagged receptor, where the two enzyme
fragments are brought within close proximity. Under these
conditions, these fragments can interact and form an active Beta-
gal enzyme complex through Enzyme Fragment Complementation
(EFC). This active Beta-gal complex can enzymatically hydrolyse
calculated separately for each individual animal.
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min post glucose dose. Glucose values were entered into an Excel
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calculated from Prism: Change from -30 to 0 BSLN Glucose, Raw
Glucose AUC-30 to 90 min, Delta Glucose AUC30 to 90 min, Raw Glucose
AUC0 to 90 min, Delta Glucose AUC0 to 90 min
.
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HPβCD and by oral gavage at 20 mg/kg in 0.5% methocel with a
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