Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists

Article abstract of DOI:10.1016/j.bmcl.2017.10.046

A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC₅₀ value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 & 32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.

Full text of DOI:10.1016/j.bmcl.2017.10.046

Accepted Manuscript
Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists
Hyojin Kim, Suk Joon Cho, Minjin Yoo, Seung Kyu Kang, Kwang Rok Kim,
Hwan Hee Lee, Jin Sook Song, Sang Dal Rhee, Won Hoon Jung, Jin Hee Ahn,
Jae-Kyung Jung, Kwan-Young Jung
PII:
S0960-894X(17)31041-7
https://doi.org/10.1016/j.bmcl.2017.10.046
BMCL 25375
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 August 2017
18 October 2017
19 October 2017
Please cite this article as: Kim, H., Cho, S.J., Yoo, M., Kang, S.K., Kim, K.R., Lee, H.H., Song, J.S., Rhee, S.D.,
Jung, W.H., Ahn, J.H., Jung, J-K., Jung, K-Y., Synthesis and biological evaluation of thiazole derivatives as GPR119
agonists, Bioorganic & Medicinal Chemistry Letters (2017), doi: https://doi.org/10.1016/j.bmcl.2017.10.046
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Bioorganic & Medicinal Chemistry Letters
jo u r n a l h o m e p a g e : w w w . e ls e v ie r . c o m
Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists
Hyojin Kim,a,† Suk Joon Cho,b,† Minjin Yoo,c Seung Kyu Kang,d Kwang Rok Kim,d Hwan Hee Lee,d Jin
Sook Song,d Sang Dal Rhee,d Won Hoon Jung,d Jin Hee Ahn,e Jae-Kyung Jung,b Kwan-Young Jungc,d,*
aDepartment of Chemistry, Sogang University, Seoul 04107, Republic of Korea
bCollege of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
cDepartment of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea
dBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
eDepartment of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their
GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione
moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d
showed good in vitro activity with an EC50 value of 49 nM and 18 nM, respectively with
improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 &
32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these
compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.
2017 Elsevier Ltd. All rights reserved.
Keywords:
GPR119 agonists
Type 2 diabetes
4-(Phenoxymethyl)thiazole
Pyrrolidine-2,5-dione
OGTT
Regulation of glucose homeostasis is crucial to mammalian
life. Insulin secretion from pancreatic ß-cells regulates increases
in glucose levels and glucose uptake in peripheral tissues. Insulin
resistance, which refers to the inability of body tissues to respond
properly to endogenous insulin, develops because of several
factors, including genetics, obesity, increasing age, and the
presence of high blood sugar over a long period of time.1 These
factors finally cause one of the most serious chronic diseases,
type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes),
which eventually induces various complications such as renal
failure, blindness, neuropathy, and cardiovascular disorders.2
More than 90% of patients with diabetes are classified as having
T2DM and the number of people with T2DM is expected to
increase to 330 million by 2030.3 Currently, various types of
hypoglycemic agents, including sulfonylureas, thiazolidinediones,
glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4
(DPP4) inhibitors, and sodium-glucose transporter-2 (SGLT-2)
inhibitors, are used for the treatment of T2DM.4 However, some
patients still fail to achieve desired blood glucose levels despite
the use of these agents. Most of these drugs cause side effects,
including hypoglycemia, weight gain, and loss of therapy
responsiveness.5 Therefore, there is a clear need for a drug with a
new mechanism of action that demonstrates improved efficacy
and safety over currently available drugs.
Figure 1. General pharmacophore model for GPR119 agonists in clinical
trials and their structures.
1

GPR119 is a member of the G protein-coupled receptor family,
and is highly expressed in pancreatic ß-cells and intestinal
endocrine cells.6 It has been proposed that GPR119 agonists
modulate glucose homeostasis by indirectly stimulating glucose-
dependent insulin release through enhancing pancreatic cell
function and releasing incretin hormones from the small
intestine.7 Coupled with the ability to enhance insulin secretion
only when glucose levels are elevated, its selective expression
makes GPR119 a very attractive target for the development of
new drugs for T2DM. Recently, a large number of synthetic low-
molecular weight GPR119 agonists have been synthesized and
compounds, such as MBX-2982, GSK1292263, APD668,
compound, which was developed as a GPR119 agonist, with various
functional groups. Commercially available 5-bromo-2-
chloropyrimidine was coupled with ethyl acrylate by Heck
reaction10 in the presence of Pd(OAc)2 catalyst to yield 6, which
was reduced using Pd/C under a hydrogen atmosphere to obtain
compound 7. N-Boc-piperidine-4-carboxamide (compound 8)
was converted to N-Boc-piperidine-4-carbothioamide (compound
9) using Lawesson's reagent after protecting the nitrogen atom
present in 4-piperidinecarboxamide with Boc anhydride.11
Compound 10 was synthesized by reacting compound 9 with 1,3-
dichloroacetone to form a thiazole ring. Compound 11 was
obtained by reacting compound 10 with 4-(1H-tetrazol-1-yl)
phenol in the presence of base.12 The Boc protecting group of
compound 11 was removed using HCl to obtain compound 12.
This compound was reacted with compound 7 to synthesize
compound 15, which obtained an acid functional group through
hydrolysis. Compound 15 was coupled with various amines using
HBTU to produce amide 16a−g.13 Compound 16d, which had an
azide group in the ethylene glycol moiety, synthesized compound
16e with had an amine through Pd/C and H2 reduction.14 We
synthesized compound 13 by reacting a portion of MBX-2982
with a biguanide group,15 the main component of the drug,
metformin, which is currently used for treating T2DM.
APD597, and BMS-903452, have entered clinical trials.8
A
general structure of the GPR119 agonist, consisting of the head,
linker, and tail moieties, was proposed. The head portion had an
aromatic ring containing an electron withdrawing group (EWG),
such as a sulfonyl group or a fluorine atom. The tail moiety had a
piperidine group with a bulky carbamate or its bioisostere9
(Figure 1).
In our efforts to discover pharmacologically superior GPR119
agonists, thiazole compound MBX-2982 was selected as a lead
structure and planned to replace the head, linker and tail moieties
to the diverse functional groups (Scheme 1–3). With this purpose,
we introduce the synthesis and biological evaluation of a series of
thiazole derivatives containing pyrrolidine-2,5-dione as the EWG
and the optimization of the head and tail moieties as potential
GPR119 agonists for the treatment of T2DM.
Table 1 shows the activity evaluation results of MBX-2982
and the tail moiety modified thiazole derivatives. As shown,
MBX-2982 showed 91% activation at 1 μM compared to
GSK1292263, which was used as a reference molecule in the
efficacy evaluation. In addition, the EC50 value for human
GPR119 is 87 nM. Compound 13 was a novel compound
synthesized by combining part of MBX-2982 with part of a
The general synthetic procedures are outlined in Schemes 1–3.
GPR119 agonist activity was evaluated by replacing the ethyl group
present in the pyrimidine ring of the tail moiety of the MBX-2982
o
Scheme 1. Reagents and conditions: (a) Pd(OAc)2, DIPEA, tri(o-tolyl)phosphine, DMF, 115 C, 3 h, 74%; (b) H2(g), Pd/C, EtOAc, r.t., 4h, 90%; (c) Boc2O,
DMAP, CH2Cl2, r.t., 2 h, 80%; (d) Lawesson’s reagent, DME/CH2Cl2 (3:1), r.t., 1 h, 55%; (e) 1,3-dichloroacetone, MgSO4, MgCO3, acetone, reflux, 12 h,
92%; (f) 4-(1H-tetrazol-1-yl)phenol, Cs2CO3, KI, acetonitrile, reflux, 12 h, 78%; (g) 4M HCl in 1,4-dioxane, CH2Cl2/MeOH (1:1), 0 oC to r.t., 7 h, 88%; (h)
o
o
dicyadiamide, conc. HCl, n-butanol, reflux, 8 h, 52%; (i) 7, K2CO3, DMF, 90 C, 4 h, 47%; (j) LiOH-H2O, THF/MeOH/H2O (3:1:1), 0 C, 3 h, 99%; (k) R1-
NH2, HBTU, DIPEA, DMF, r.t., 12 h, 36–95%.
2

biguanide, but it did not activate GPR119. Compound 15 (with
an acid functional group), compound 16a (with
trimethylammonium chloride salt), and compound 16e (with an
ethylamine moiety) did not show any activity. Thereafter, we
conducted an experiment to convert the tail moiety to an
ethylpyrimidine group and modify the head moiety.
by reacting hydroxybenzaldehyde with fluorine, hydrogen, or a
methyl group with compound 10. Compounds 30a–d were
synthesized by reacting with 3-(triphenylphosphoranylidene)
succinimide.17 Compounds 31a–d, obtained by removing the Boc
protection group via treatment with HCl, were reacted with 2-
chloro-5-ethylpyrimidine to synthesize compounds 32a, c, and d.
Compounds 31a–d were reacted with isobutylene oxide18 to
synthesize compounds 33a–d. Compounds 34a–d were obtained
by treating the hydroxyl group with a fluorine group using
Deoxo-Fluor®.19
a
GPR119 agonists have a strong hydrogen bond acceptor, such
as a methyl sulfonyl or tetrazole group, in the head moiety. We
synthesized compounds containing methylsulfonyl or tetrazole
surrogates as novel hydrogen bonding acceptors in GPR119
agonists (Scheme 2). To identify novel sulfone or tetrazole
surrogates, various functional groups, including 2,4-
thiazolidinedione, rhodanine, 3-aminorhodanine, carboxylic acid,
pyrrolidin-2-one, and pyrrolidine-2,5-dione, were introduced on
the aromatic ring. Compound 10 was reacted with 3-fluoro-4-
hydroxyphenol to afford compound 17. The Boc group was
removed by treatment with HCl and reaction with 2-chloro-5-
ethylpyrimidine to afford compound 19. Compound 19 and
various kinds of heterocyclic compounds were reacted using the
Knoevenagel condensation reaction16 to obtain compounds
20−27. To obtain compound 27, 3-(triphenylphosphoranylidene)
succinimide was synthesized by reacting maleimide with
triphenylphosphine,17 then compound 19. Compound 26 was
obtained by reacting 1-acetylpyrrolidin-2-one with tert-BuOK
and compound 19. Compound 28a–d having morpholine,
tetrahydropyran or aminoalkyl chain as a head moiety were
synthesized using alkylation with compound 27.
Introduction of 2,4-thiazolidinedione as the polar head
resulted in compound 20, which had weak GPR119 agonistic
potency (% activation relative to GSK1292263 (100%) at 1 μM)
and an EC50 = 780 nM (Table 2). Compounds containing polar
head moieties with rhodanine (21), 3-aminorhodanine (22), or
carboxylic acid (23) had no agonistic effects. Compound 25,
containing a 3-phenyl pyrrolidin-2,5-dione polar head group, had
a potency comparable to that of MBX-2982. Pyrrolidine-2,5-
dione can act as a strong hydrogen bond acceptor and replace the
surrogate of the tetrazole group of MBX-2982. To demonstrate
this, we removed the bulky phenyl group from 3-phenyl
pyrrolidin-2,5-dione and found that the activity of compound 27
increased to EC50 = 49 nM. Pyrrolidin-2-one is a C=O group-
absent form present in pyrrolidine-2,5-dione. Compared with
compound 26, the agonistic effect of compound 27 was 2-fold
increased. However, when phenyl, morpholine, tetrahydropyran,
or aminoalkyl chains were attached to the nitrogen position of the
pyrrolidine-2,5-dione, potency was decreased compared to that of
compound 27.
After the synthesis of methylsulfonyl or tetrazole surrogate
derivatives, compounds synthesized by introducing hydrogen,
fluoro, and methyl groups into the head group of GPR119
agonists were synthesized. Compounds 29a–d were synthesized
Scheme 2. Reagents and conditions: (a) Cs2CO3, KI, acetonitrile, reflux, 12 h, 77%; (b) 4M HCl in 1,4-dioxane, CH2Cl2/MeOH (1:1), 0 oC to r.t., 7 h, 96%; (c)
2-chloro-5-ethylpyrimidine, K2CO3, DIPEA, DMF, 90 oC, 4 h, 73%; (d) heterocyclic compounds, piperidine, ethanol, reflux, 2 h, 25–88%; (e) R2-Br, K2CO3, KI,
DMF, r.t., 5 h or R2-OH, DIAD, PPh3, THF, r.t., 5 h, 56–75%.
3

Scheme 3. Reagents and conditions: (a) Cs2CO3, KI, acetonitrile, reflux, 12 h, 72–85%; (b) piperidine, ethanol, reflux, 2h, 72–88%; (c) 4M HCl in 1,4-dioxane,
CH2Cl2/MeOH (1:1), 0 oC to r.t., 7 h, 94–97%; (d) 2-chloro-5-ethylpyrimidine, K2CO3, DIPEA, DMF, 90 oC, 1 h, 36–48%; (e) isobutylene oxide, DIPEA,
THF/MeOH (1:1), 60 oC, 12 h, 67–93%; (f) Deoxo-Fluor, CH2Cl2, r.t., 2h, 30–47%.
Table 1. GPR119 agonist activity of thiazole derivatives with tail moiety variations
%
%
hGPR119
EC50 (nM)
hGPR119
EC50 (nM)
Comp
Structure
Activation
at 1 μMa
Comp
Structure
Activation
at 1 μMa
MBX
2982
91
87
16b
16c
22
26
25
ND
ND
ND
118
103
11
13
b
20
34
16d
16e
ND
ND
14
28
ND
29
28
ND
ND
16f
15
30
27
ND
ND
16g
16a
a Activation relative to GSK1292263. b Not determined.
Table 2. GPR119 agonist activity of thiazole derivatives with electron withdrawing group variations
%
%
hGPR119
hGPR119
Comp
Structure
Activation
at 1 μMa
Comp
Structure
Activation
at 1 μMa
EC50 (nM)
EC50 (nM)
60
780
26
20
65
100
b
39
43
32
27
ND
21
22
23
94
49
61
49
ND
ND
28a
28b
ND
240
55
67
ND
82
28c
28d
24
25
63
51
ND
ND
a Activation relative to GSK1292263. b Not determined.
4

Table 3. GPR119 agonist activity of thiazole derivatives with head & tail moiety variations
%
%
hGPR119
hGPR119
EC50 (nM)
Comp
30a
Structure
Activation
at 1 μMa
Comp
Structure
Activation
at 1 μMa
EC50 (nM)
b
57
69
41
81
33a
ND
27
31
32
36
ND
ND
ND
ND
157
ND
19
33b
33c
33d
34a
34b
30b
30c
30d
32a
32c
71
59
90
182
211
48
53
42
ND
ND
ND
18
34c
34d
32d
46
ND
a Activation relative to GSK1292263. b Not determined.
Table 4. Stability, CYP, hERG and cytotoxicity of compound MBX-2982, 27 and 32d.
Results
Assay
MBX-2982
27
32d
Liver microsomal
stabilitya
7.80
48.9
17.1
(Human)
Liver microsomal
stabilitya
20.6
33.0
32.4
(rat)
1A2: >100
2A6: 3.53
2C19: >100
2D6: >100
3A4: 2.24
1A2: >100
2A6: >100
2C19: >100
2D6: >100
3A4: >100
1A2: >100
2A6: >100
2C19: >100
2D6: >100
3A4: >13.8
CYP inhibition
hERGb
10.5
5.3
3.3
VERO: >100
L929: >100
NIH3T2: >100
HFL-1: >100
CHO-K1: >100
VERO: >100
L929: >100
NIH3T2: >100
HFL-1: >100
CHO-K1: >100
VERO: >100
L929: >100
NIH3T2: >100
HFL-1: >100
CHO-K1: >100
Cytotoxicityc
a % original compound remained after 30 min incubation.
b % inhibition at 10 μM (binding assay).
c IC50 (μM) values in various mammalian cell lines. Cell information. VERO: African green monkey kidney cell line, HFL-1: Human embryonic lung cell line,
L929: Mouse fibroblast cell line, NIH3T3: Mouse embryonic fibroblast cell line, CHO-K1: Chinese hamster ovary cell line.
the agonistic effect of compounds 30a–d, of which phenyl ring
was substituted with hydrogen, methyl, and difluoride groups
instead of a fluorine atom, compounds 30b and 30d, with
fluorophenyl and tolyl, had good activity, but the activity of
compounds 30a and 30c, with phenyl and difluorophenyl, was
We determined that pyrrolidine-2,5-dione was the most
appropriate functional group from the activity data shown in
Table 2. Therefore, other compounds needed to be modified by
fixing the polar head with pyrrolidine-2,5-dione. As shown by
not good. In particular, the activity of compound 32d was
5

superior to that of compound 27. Compounds 32a, c, and d were
prepared by substituting carbamate tert-butyl groups with ethyl
pyrimidine groups to improve metabolic stability. Overall,
activity was good and compound 32d (EC50 = 18 nM) with tolyl
was more active than compound 27 (EC50 = 49 nM) with a
fluorophenyl ring. Compounds 33a–d and 34a–d were obtained
by replacing ethylpyrimidine with tert-alcohol and fluorine,
respectively, in the tail moiety, but no agonistic effect was
observed.
activity for GPR119 and improved pharmacokinetic profiles.
Several compounds showed good agonistic activity (EC50 < 100
nM) and potency. Among them, compounds 27 and 32d showed
good in vitro activities with EC50 values of 49 nM and 18 nM,
respectively. These compounds did not exhibit significant CYP
inhibition, hERG binding, or cytotoxicity.
Acknowledgments
The in vitro data shown in Table 1−3 indicated that 27 and
32d should be selected as prototype compounds. Compounds 27
and 32d were evaluated for stability, ability to induce or inhibit
CYP, hERG binding, and cytotoxicity. As shown in Table 4,
compounds 27 and 32d were more metabolically stable than
MBX-2982 in human and rat liver microsomes. In CYP
inhibition assays with several CYP subtypes, compounds 27 and
32d did not significantly inhibit CYP and showed no hERG
binding. To evaluate in vivo efficacy, an oral glucose tolerance
test (OGTT) was performed with compounds 27 and 32d. Plasma
glucose levels were determined based on the AUC of the glucose
concentration and were reduced at the 30 mg/kg dose. The in vivo
efficacy of these two compounds was similar to that of MBX-
2982 (Figure 2).
This work was supported by the KRICT (KK1703-G00,
KK1707-C05, SI1707-02, KK1607-C09) and National Research
Council of Science and Technology (SKO1707C05).
† These authors contributed equally to this work.
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6

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Supplementary Material
Supplementary data associated with this article can be found,
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Graphical Abstract
Synthesis and biological evaluation of
thiazole derivatives as GPR119 agonists
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Hyojin Kim,a,† Suk Joon Cho,b,† Minjin Yoo,c Seung Kyu Kang,d Kwang Rok Kim,d Hwan Hee Lee,d Jin Sook
Song,d Sang Dal Rhee,d Won Hoon Jung,d Jin Hee Ahn,e Jae-Kyung Jung,b Kwan-Young Jungc
8