Optimization of a novel series of potent and orally bioavailable GPR119 agonists

Article abstract of DOI:10.1016/j.bmcl.2017.06.034

We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC₅₀?=?129?nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC₅₀?=?53?nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC₅₀?=?42?nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10?mg/kg in an oral glucose tolerance test in C57BL/6N mice.

Full text of DOI:10.1016/j.bmcl.2017.06.034

Accepted Manuscript
Optimization of a novel series of potent and orally bioavailable GPR119 agonists
Tomoaki Koshizawa, Toshiharu Morimoto, Gen Watanabe, Toshiaki Watanabe,
Nao Yamasaki, Yoshikazu Sawada, Tomoaki Fukuda, Ayumu Okuda, Kimiyuki
Shibuya, Tadaaki Ohgiya
PII:
S0960-894X(17)30636-4
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.06.034
BMCL 25068
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 April 2017
6 June 2017
12 June 2017
Please cite this article as: Koshizawa, T., Morimoto, T., Watanabe, G., Watanabe, T., Yamasaki, N., Sawada, Y.,
Fukuda, T., Okuda, A., Shibuya, K., Ohgiya, T., Optimization of a novel series of potent and orally bioavailable
GPR119 agonists, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2017.06.034
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Bioorganic & Medicinal Chemistry Letters
Optimization of a novel series of potent and orally bioavailable GPR119 agonists
Tomoaki Koshizawa, Toshiharu Morimoto, Gen Watanabe, Toshiaki Watanabe, Nao Yamasaki, Yoshika-
zu Sawada, Tomoaki Fukuda, Ayumu Okuda, Kimiyuki Shibuya and Tadaaki Ohgiya
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., LTD., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G
protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50 = 129 nM) was improved by
replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen
in the head moiety with a covalent C-C bond to enhance conformational restriction, which con-
sequently gave a lead compound 12 (EC50 = 53 nM). Optimized compound 26, which was iden-
tified by the further optimization of 12, exhibited potent activity (EC50 = 42 nM) with improved
clearance in liver microsomes and induced a 33% reduction in blood glucose area under the
curve at a dose of 10 mg/kg in an oral glucose tolerance test in C57BL/6N mice.
Keywords:
GPR119 agonists
Type 2 diabetes mellitus
Furo[3,2-d]pyrimidine
Intramolecular hydrogen bond
Restricted conformation
2017 Elsevier Ltd. All rights reserved.
Diabetes mellitus (DM) is a chronic disease that eventually
causes various complications, such as cardiovascular disorders,
blindness, neuropathy, and renal failure, due to prolonged hyper-
glycemia caused by insulin resistance and/or insufficient insulin
secretion.1 More than 90% of diabetic patients are classified as
having type 2 DM (T2DM). The number of patients with T2DM
is expected to increase to 330 million by 2030.2 Many different
hypoglycemic agents, such as sulfonylureas, thiazolidinediones,
glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4
inhibitors, and sodium-glucose transporter-2 inhibitors, are used
for the treatment of T2DM.1,3 However, some patients fail to
achieve the desired blood glucose levels despite using conven-
tional hypoglycemics. Most of these drugs cause adverse effects
such as hypoglycemia, weight gain, and loss of therapy respon-
siveness. Therefore, there are still significant unmet medical
needs for treating T2DM.
ing drug targets for the treatment of T2DM. Indeed, many
groups have investigated GPR119 agonists.8 A general struc-
ture of GPR119 agonists consisting of head, linker, and tail moie-
ties was proposed (Figure 1).8,9 The head moiety has an aromatic
ring substituted with electron-withdrawing groups such as a
sulfonyl group and/or a fluorine atom, and the tail moiety has a
piperidine group with a bulky alkyl carbamate or its bioisostere.
Figure 1. General structure of GPR119 agonists.
In this paper, we describe the synthesis and biological evalua-
tion of a series of compounds with furo[3,2-d]pyrimidine as the
linker and the optimization of the head and tail moieties. For the
former optimization, molecular design based on conformational
requirements was applied.
G protein-coupled receptor 119 (GPR119) is predominantly
expressed in pancreatic -cells and intestinal L-cells.4 The activa-
tion of GPR119 promotes insulin secretion from pancreatic -
cells and the release of GLP-1 from intestinal L-cells. The insu-
lin-releasing effect is glucose-dependent; hence, the associated
risk of hypoglycemia is expected to be low.5 Besides the
above,-cell function preservation, which is assumed to be a
critical target in current T2DM treatment,6 as well as body-
weight reduction based on the secretion of GLP-1 are shown in
animal models.5b,7 These effects make GPR119 agonists promis-
During our efforts to discover small molecule GPR119 ago-
nists, we first sought a novel linker moiety containing a bicyclic
pyrimidine scaffold based on structures of reported compounds,
for example, 1, 2, and 3 (Figure 2)10-12 and found furo[3,2-
d]pyrimidine as a promising structure. Furo[3,2-d]pyrimidine
derivative 4 exhibited the most potent human GPR119 agonistic
———
 Corresponding author. Tel.: +81-42-391-6211; fax: +81-42-395-0312; e-mail: t-kosizw@kowa.co.jp

Figure 3. Importance of fluorine atom in 2-fluoro-4-(methylsulfonyl)aniline.
Figure 2. GPR119 agonists possessing bicyclic pyrimidines. Data
fluorine atom is a poor hydrogen bond acceptor;18 hence, we as-
sumed that the cyclization by replacing the H-F hydrogen bond
with a covalent C-C bond would enhance the rigidity to elevate
the potency of 4, and designed annulated anilines 5.
in parentheses are cited from the literature.
activity (EC50 = 129 nM, Emax = 123%) in our first group of
GPR119 agonists13 and showed 13% reduction in blood glucose
area under the curve (AUC) at a dose of 30 mg/kg in an oral glu-
cose tolerance test in C57BL/6N mice.
To investigate which structural features of the head moiety
would be required for potent GPR119 agonistic activity, a series
of compounds containing furo[3,2-d]pyrimidine as the linker
were synthesized (Scheme 1).19 N-Boc protection of 6 followed
by mesylation with MsCl gave the corresponding mesylate,
which was transformed with sodium cyanide into nitrile 7 in 77%
yield based on 6. Lithiation of 7 with lithium diisopropylamide
(LDA) followed by formylation gave enolate 8 in 92% yield.
Furan 9 was prepared by cyclization with diethyl chloromalonate
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 50% yield, and
the following condensation with formamidine acetate yielded
furo[3,2-d]pyrimidine 10 in 56% yield. Activation of the hydroxy
group of 10 was achieved with (benzotriazol-1-yloxy)tripyrrolid-
inophosphonium hexafluorophosphate (PyBop) to give interme-
diate 11 in 83% yield. Nucleophilic displacement reactions of 11
with the corresponding anilines and heterocyclic compounds20
afforded 4 and 12–16, respectively (13–91%).21
We next focused on the optimization of the head moiety and
noticed the fluorine atom at the C2 position in 2-fluoro-4-
(methylsulfonyl)aniline, which plays a pivotal role in enhancing
potency against GPR119 (Figure 3). Semple et al. reported that
AR231453 (R1 = F, R2 = H) exhibited approximately eight times
more potent activity than the non-substituted compound (R1, R2 =
H).14 However, fluorine substitution at the C3 position (R1 = H,
R2 = F) hardly led to an improvement of potency. Park’s study
also showed that the fluorinated compound at the C2 position (R
= F) was superior in activity to the non-substituted derivative (R
= H).15
We hypothesized that the fluorine atom at the C2 position in-
duced conformational restriction by the intramolecular hydrogen
bond between the fluorine atom and the aniline hydrogen atom16
(Figure 4) because a number of studies have proposed that con-
formational rigidity contributes to high potency.17 However, a
Figure 4. Design of annulated aniline 5 by fixing the conformation at the head moiety.
Scheme 1. Synthesis of compounds 4 and 12–16. Reagents and conditions: (a) Boc2O, Na2CO3, THF, H2O, rt, overnight; (b) MsCl, Et3N, THF, 0 °C,
15 min; (c) NaCN, EtOH, H2O, 80 °C, 24 h, 77% (3 steps); (d) (i) LDA, THF, −78 °C, 1 h; (ii) ethyl formate, −30 °C to rt, overnight, 92%; (e) (i)
diethyl chloromalonate, DMF, rt, 24 h; (ii) DBU, EtOH, rt, 3 h, 50%; (f) formamidine acetate, EtOH, reflux, 2 days, 56%; (g) PyBop, DBU, THF, rt,
30 min, 83%; (h) anilines or heterocyclic compounds, NaH, DMF, 0 °C-100 °C, 13–91%.

Table 1 Effects of intramolecular hydrogen bond and structural
requirements at head moiety.
putational calculation using molecular dynamics software24 sug-
gested that C2-C1-N-R(C1′) of 4, 12, and 13 were arranged in
periplanar/clinal, periplanar, and clinal conformations, respec-
tively. The calculated results are shown in Figure 5. Estimated
distribution of dihedral angles of C2-C1-N-R(C1′) of 4 (purple),
12 (red), and 13 (blue) were, −60° to +60°, −30° to +30°, and
−180° to −30° (partially +30° to +180°), respectively, and these
results suggested the principal conformation of each compound
as mentioned above. Based on these results, we considered that
the conformational restriction of C2-C1-N-R(C1′) in periplanar
arrangement was a requisite for high agonistic activity. From this
perspective, the six-membered ring system in 14 was expected to
show activity comparable with that of the five-membered ring
system in 12 because the computational calculation suggested
that the C2-C1-N-C1′ of 14 (green in Figure 5) was also arranged
in a periplanar conformation, as in 12 (red in Figure 5). However,
contrary to expectations, tetrahydroquinoline derivative 14 did
not show significant activity. A plausible explanation for this is
that loss of planarity around the annulated part in the head moiety
hGPR119 agonistic activities
Com-
EC50 (nM)a
Emax (%)b
pound
4
129
123
12
13
14
15
16
53
123
was caused by
a
half-chair conformation of the
tetrahydroquinoline ring. In this series of compounds,
dimethylindoline derivatives 15 and 16 also showed diminished
activity. The loss of potency was probably caused by steric hin-
drance of the dimethyl groups on the indoline scaffold. We con-
sidered that planarity of the head moiety, not only the conforma-
tional restriction discussed above but also less steric bulkiness
around the annulated part of the moiety, was a crucial structural
requirement for a potent GPR119 agonist. Consequently, we se-
lected 5-(methylsulfonyl)indoline as an optimal unit for the head
moiety.
>1000
6
1
-
793
not active
not active
-
a
Assay values are reported from a single determination performed in
quadruplicate. See Ref. 22 for the assay protocol.
b Emax was defined as the percentage ratio between the maximum re-
sponse for the test compound and the response for AR231453 at 100 nM.
Compounds 12–16 were evaluated (Table 1). As expected,
annulated compound 12 containing the 5-(methylsulfonyl)
indoline motif23 was more potent (EC50 = 53 nM, Emax = 123%)
than 4. In contrast, N-methylated aniline 13 showed depletion of
the agonistic activity. Along with these experimental findings,
com-
Figure 5. Distribution of dihedral angle at the head moiety.
Scheme 2. Synthesis of furo[3,2-d]pyrimidine derivatives 18–26. Reagents and conditions: (a) 4N HCl in AcOEt, MeOH, CHCl3, rt, 1.5 h, 73%; (b) for 18,
20, 21, 25 and 26: 2-chloropyrimidine derivatives, DIEA, DMF or IPA, rt to 100 °C, 15–98%; (c) for 19: (i) 5-bromo-2-chloropyrimidine, DIEA, DMF, 100
°C,12 h, 84%; (ii) MeB(OH)2, Pd(dppf)Cl2·CH2Cl2, Cs2CO3, THF, DMF, 100 °C, 12 h, 26%; (d) for 23: (i) 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyrimidine, IPA, reflux, overnight; (ii) H2O2, THF, rt, overnight, 27% (2 steps); (e) NaBH4, MeOH, CH2Cl2, 0 °C to rt, 0.5 h, 80%; (f)
MeI, K2CO3, DMF, rt, 1 h, 16%.

Table 2 Optimizing study on the tail moiety.
cumvent this drawback, we focused on 5-substituted pyrimidines,
which were recently reported as bioisosteres of carbamates.25 5-
Substituted pyrimidine derivatives 18–26 were prepared as
shown in Scheme 2. N-Boc deprotection of 12 under acidic con-
ditions afforded hydrochloride salt 17 in 73% yield. Pyrimidine
derivatives 18–26 were synthesized from hydrochloride salt 17
by a nucleophilic displacement reaction with the corresponding
2-halopyrimidines.
hGPR119
c
LMClint
agonistic activities
Com-
pound
Z
Although 20 exerted higher activity (EC50 = 41 nM, Emax
=
EC50
Emax
154%, Table 2) than 12, the metabolic instability of 20 assessed
by clearances in both human and mouse liver microsomes was
increased (412 and 187 l/min/mg/protein in human and mouse,
respectively). Because plausible metabolites of 20 (21 and 22)
were less potent, these compounds as well as 20 could not be
regarded as candidates for further evaluation. The unpromising
potency of 23 and 24 also suggested intolerance for the introduc-
tion of a hydrophilic group at the 5-position. To fulfill both re-
quirements, namely, potency and metabolic stability, substitution
with a halogen atom at this position was examined. Although 5-
fluoropyrimidine 25 exhibited moderate EC50 (201 nM), 5-
chloropyrimidine 26 showed potent GPR119 agonistic activity
(EC50 = 42 nM, Emax = 117%). Moreover, compound 26 showed
improved human and mouse liver microsome clearances (113 and
108 l/min/mg/protein). We assumed that the improvement in
metabolic stability by the replacement of the ethyl group by a
chlorine atom was mainly caused by the removal of the carbon
atom adjacent to the aromatic ring, which is generally susceptible
to oxidative metabolism.26 Consequently, compound 26 was se-
lected and evaluated further as the most promising GPR119 ago-
nist in the optimization in vitro.27
human
550
NTd
349
412
74
mouse
508
NTd
145
187
154
66
(nM)a
(%)b
12
18
19
20
21
22
23
24
25
26
-CO2-
tBu
H
53
512
252
41
123
196
159
154
12
Me
Et
Ac
78
586
391
310
201
42
33
102
132
255
257
113
OH
OMe
F
145
186
229
117
107
189
154
108
The pharmacokinetic properties of 26 are shown in Table 3.
Compound 26 possessed a good pharmacokinetic profile in mice,
and lowered the blood glucose excursion at a dose of 10 mg/kg in
an oral glucose tolerance test in C57BL/6N mice (Figure 6). The
reduction of blood glucose AUC was 33%, which was 20% high-
er than the results obtained upon 30 mg/kg administration of lead
compound 4.
Cl
a Assay values are reported from a single determination performed in quadru-
plicate. See ref. 22 for the assay protocol.
Table 3. Pharmacokinetic parameters of 26 in mice.a
b Emax was defined as the percentage ratio between the maximum response for
the test compound and the response for AR231453 at 100 nM.
CLp iv
Vss iv
(L/kg)
2.3
t1/2 iv
(h)
Cmax po
(ng/ml)
2015
AUC po
(ng h/ml)
9386
BAb
(%)
37
c Liver microsome clearance (l/min/mg/protein).
(ml/min/kg)
d Not tested.
6.5
5.1
a
We then focused on the optimization of the tail moiety. Alt-
hough our pivotal compound 12 exerted potent in vitro agonistic
activity, Boc group in the moiety was not suitable for oral admin-
istration because of its lability under acidic conditions. To cir-
26 was dosed at 0.5 mg/kg (iv) and 10 mg/kg (po) in vehicle of PET
(80% PEG400, 10% ethanol, 10% Tween80TM).
b Bioavailability.
Figure 6. Effect of 26 (10 mg/kg) on glucose excursion in an oral glucose tolerance test in C57BL/N mice. 26 was administered in PET 25 min prior to
glucose loading at 3 g/kg. Glucose levels were monitored for 120 min. * indicates a p value of <0.01.

In summary, we conducted optimization of the lead compound
4 and obtained 26 as a drug candidate of a GPR119 agonist for
further evaluations. We noticed the pivotal role of the fluorine
atom in 2-fluoro-4-(methylsulfonyl)aniline at the head moiety of
4, based on the analysis that the intramolecular hydrogen bond
between the fluorine atom and the aniline hydrogen was associat-
ed with the restriction of conformation, and found 5-
(methylsulfonyl)indoline as an optimal unit for the moiety. We
considered that planarity of the head moiety, involving not only
the conformational restriction but also less steric bulkiness
around the annulated part of the moiety, was a crucial structural
requirement for a potent GPR119 agonist. The optimized com-
pound 26 showed potent GPR119 agonistic activity (EC50 = 42
nM, Emax = 117%) with improved liver microsome clearance, and
exerted 33% reduction in blood glucose AUC at a dose of 10
mg/kg in an oral glucose tolerance test in C57BL/6N mice. Fol-
low-up studies and their results will be reported in due course.
hGPR119 agonistic activities
X
Y
EC50 (nM)
79
Emax (%)
S
NH
NMe
O
C
C
C
N
82
9
>1000
>1000
353
3
137
14. Semple, G.; Fioravanti, B.; Pereira, G.; Calderon, I.; Uy, J.; Choi,
K.; Xiong, Y.; Ren, A.; Morgan, M.; Dave, V.; Thomsen, W.;
Unett, D. J.; Xing, C.; Bossie, S.; Carroll, C.; Chu, Z.-L.; Grottick,
A. J.; Hauser, E. K.; Leonard, J.; Jones, R. M. J. Med. Chem.
2008, 51, 5172.
15. Yang, Z.; Fang, Y.; Pham, T.-A. N.; Lee, J.; Park, H. Bioorg. Med.
Chem. Lett. 2013, 23, 1519.
Acknowledgments
16. Li, C.; Ren, S.-F.; Hou, J.-L.; Yi, H.-P.; Zhu, S.-Z.; Jiang, X.-K.;
Li, Z.-T. Angw. Chem. Int. Ed. 2005, 44, 5725. Downfield chemi-
cal shift of the NH signal of compound 4 (δ 7.42 ppm) compared
with that of the non-substituted compound (δ 7.36 ppm) suggested
the formation of the H-F intramolecular hydrogen bond.
17. (a) Kobayashi, T.; Suemasa, A.; Igawa, A.; Ide, S.; Fukuda, H.;
Abe, H.; Arisawa, M.; Minami, M.; Shuto, S. Med. Chem. Lett.
2014, 5, 889; (b) Bakali, J. E.; Muccioli, G. G.; Body-Malapel,
M.; Djouina, M.; Klupsch, F.; Ghinet, A.; Barczyk, A.; Renault,
N.; Chavatte, P.; Desreumaux, P.; Lambert, D. M.; Millet, R. Med.
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Y. Mar. Drugs 2016, 14, 85.
We thank Dr. S. Tanabe, Director of Tokyo New Drug Re-
search Laboratories, Executive Officer, Member of the Board,
Kowa Co., Ltd., for his support and encouragement.
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21. Yields of the final step depend on the reactivity of the substrates.
For example, compound 15 was obtained in low yield (13%)
probably due to the steric hindrance of the dimethyl group.
22. The assay consists of CHO-K1 CRE-luciferase cells that stably
express human GPR119 receptor plated at 20,000 cells/well in 80
µL of Ham’s F12 Nutrient Mixture and 0.1% fetal bovine serum
in white 96-well assay plates. On the following day, 20 μl of test
compounds are pipetted into the assay plates. The plates are then
incubated for 4 h at 37 °C. According to the Bright-Glo™ Lucif-
erase Assay System (Promega), the amount of luciferase generated
is quantified in a Centro LB960. Compounds are also tested in the
same manner against cells without the GPR119 receptor so as to
check for false positives. Reliability of the data was confirmed by
visual inspection of the viability of cells during the assay.
23. Sato, K.; Sugimoto, H.; Rikimaru, K.; Imoto, H.; Kamaura, M.;
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on patent applications. The EC50 values of the compounds range
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26. Metabolic stability predictions were performed with StarDrop
(Optibrium. StarDrop. www.optibrium.com/stardrop). The calcu-
lation suggested that the ethyl group of compound 20 was easily
metabolized by cytochrome P450.
27. The cytotoxicity of compound 26 against CHO-K1 cells was as-
sessed by Cell Counting Kit-8 (Dojindo Laboratories, Kumamoto,
Japan). The IC50 value was >10 M.
13. The other 6,5-fused bicyclic pyrimidines as the linker were evalu-
ated for human GPR119 agonistic activities.

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Optimization of a novel series of potent and
orally bioavailable GPR119 agonists
Leave this area blank for abstract info.
Tomoaki Koshizawa*, Toshiharu Morimoto, Gen Watanabe, Toshiaki Watanabe, Nao Yamasaki, Yoshikazu
Sawada, Tomoaki Fukuda, Ayumu Okuda, Kimiyuki Shibuya and Tadaaki Ohgiya