2,5-Disubstituted pyridines as potent GPR119 agonists

Article abstract of DOI:10.1016/j.bmcl.2010.02.083

A series of 2-piperazinyl-5-alkoxypyridines were synthesized and screened against human GPR119 receptor. Through SAR analysis, compounds containing 2-alkylsulfonylpiperazinyl-5-alkoxypyridines were discovered and found to be potent agonists of the human GPR119 receptor.

Full text of DOI:10.1016/j.bmcl.2010.02.083

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2577–2581
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2,5-Disubstituted pyridines as potent GPR119 agonists
*
*
Yulin Wu , Judith D. Kuntz , Andrew J. Carpenter , Jing Fang, Howard R. Sauls, Daniel J. Gomez,
Carina Ammala à, Yun Xu §, Shane Hart –, Sarva Tadepalli ||
GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-piperazinyl-5-alkoxypyridines were synthesized and screened against human GPR119
receptor. Through SAR analysis, compounds containing 2-alkylsulfonylpiperazinyl-5-alkoxypyridines
were discovered and found to be potent agonists of the human GPR119 receptor.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 January 2010
Revised 19 February 2010
Accepted 22 February 2010
Available online 25 February 2010
Keywords:
GPR119 receptor
Type 2 diabetes
SAR
GPR119 is a Family A, G protein-coupled receptor (G
a
s) pre-
Ltd. The field of GPR119 agonist research has progressed far en-
ough for some companies to push compounds into the clinic. For
example, Arena and partner Ortho-McNeil initiated the earliest
FTIH studies with APD668 and have recently progressed APD597
into phase I clinical trials.11 Prosidion and Metabolex have also an-
nounced clinical trials with GPR119 agonists with PSN821 and
MBX-2982, respectively.12,13 With early, positive reports on its
clinical utility, the long-term efficacy and safety of this new class
of therapeutic agents for the treatment of T2D will eventually dic-
tate the future for GPR119 agonists.
dominantly expressed in pancreatic islets and gastrointestinal
(GI) tract.1–5 The tissue distribution suggests that GPR119 could
be involved in the control of incretin and islet hormone release,
and the regulation of glucose control. In fact, endogenous peptides
and small molecule GPR119 agonists have both been shown to eli-
cit insulinotropic effects in vitro.5–7 It has also been reported that
small molecule GPR119 agonists can promote incretin secretion
contributing to lowering plasma glucose levels during an oral glu-
cose tolerance test.5–7 Furthermore, there is evidence to support
the role of GPR119 agonists in slowing gastric emptying, reducing
food intake and promoting weight loss, possibly through the ac-
tions of GLP-1 release, although it has been reported that not all
GPR119 agonists demonstrate these effects.5–7
While the details of the mechanism of action of this receptor are
not yet fully understood, GPR119 is nonetheless emerging as an
attractive target for the treatment of diabetes. Likely reflecting
the broad interest in modulating GPR119 receptor signaling for a
therapeutic benefit, many synthetic GPR119 agonists have been re-
ported in the past several years.8–10 Two of the earlier GPR119 ago-
nists with significant, published preclinical data are AR231453 (1)
from Arena Pharmaceuticals and PSN632408 (2) from Prosidion
We identified a series of dihydropyrrolopyrimidines (DHPP)14
and biaryl compounds15 as GPR119 agonists. Parallel to our efforts
on the biaryl series, we began to explore 2-piperazinyl-5-alkoxy-
pyridines, represented by generic structure 3, with the hope of
identifying a template with superior solubility, thus improving
the overall pharmacokinetic properties over existing series. Coinci-
dentally, a patent application from IRM LLC that claimed a series of
GPR119 receptor agonists with similar or identical structures with
our compounds was recently published.16 Herein we report the
synthesis and structure–activity relationships (SAR) of this novel
series of compounds.
The synthesis of this series of compounds started from Boc-pro-
tected piperidinylalkyl alcohol 4 (Scheme 1). Mesylation of 4 with
methanesulfonyl chloride in the presence of triethylamine pro-
vided intermediate 5. Displacement of the mesylate with commer-
cially available 2-bromo-5-hydroxypyridine (6) in the presence of
a base provided key intermediate 7. This two-step sequence was
preferred over a one-step Mitsunobu reaction (DIAD, PPh3, THF)
due to purification issues.
* Corresponding authors. Tel.: +1 919 483 9561.
E-mail addresses: yulin.x.wu@gsk.com (Y. Wu), andrew.j.carpenter@gsk.com
(A.J. Carpenter).
Present address: 8 New Village Road, Woburn, MA 01801, USA.
Present address: AstraZeneca, Mereside Alderley Park, Macclesfield, Cheshire
SK10 4TG, UK.
à
§
Present address: 4740 Bradley Blvd. #206, Chevy Chase, MD 20815, USA.
Present address: 30014 Edgewood Dr, Georgetown, TX 78628, USA.
Present address: Duke Medical Center, Durham, NC 27705, USA.
In order to functionalize the 2-position of the pyridine ring of
intermediate 7, a set of substituted piperazines was required.
–
||
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.083

2578
Y. Wu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2577–2581
O
O
S
O
O
N
N
O
N
O
N
N
N
N
NO2
F
N
N
N
O
1
2
R
N
N
N
(
)
n
O
N
R'
3
Br
N
Br
N
( )n
( )n
MsO
HO
( )n
OH
O
i
N
O
N
O
6
N
O
O
O
ii
O
4
5
7
Scheme 1. Synthesis of intermediate 7 (n = 0–2). Reagents: (i) MsCl, Et3N, DCM; (ii) 6, K2CO3, DMF.
tency compared to alkylsulfonamides. The data in Table 1 indicated
the trend of descending potency was in the order of: cyclohexylm-
ethyl (23) > n-butyl (20) > cyclohexyl (22) > n-propyl (19) ꢀ iso-
propyl (18) > ethyl (17). Generally speaking, non-polar alkylsulf-
onamide end groups conferred better GPR119 agonism.
One of the relatively potent compounds in Table 1 is carbamate
19. Efforts to find the optimal fragments on the substituted piper-
idine were focused on the replacement of the carbamate with
amides and ureas. However, switching from isopropyl carbamate
(Table 2) to isopropyl urea 28 lowered potency by about threefold
iii
i or ii
HN
R
N
R N
NBoc
NBoc
NH
8
9
10
Scheme 2. General synthetic process for substituted piperazine 10. Reagents: (i)
alkyl halides, K2CO3, DMF; (ii) acyl or sulfonyl chloride, Et3N, DCM; (iii) 4 M HCl in
1,4-dioxane or TFA, DCM.
These substituted piperazines were generally synthesized in a two-
step process (Scheme 2). The first step involved reacting N-Boc-
protected piperazine 8 with commercially available alkyl halides
and acyl or sulfonyl chlorides under basic conditions to afford
intermediate 9. Acid treatment of compound 9 with either hydro-
gen chloride or TFA, followed by washing with sodium bicarbonate
solution, provided substituted piperazine 10.
(from EC50 = 0.3 lM to 1.0 lM). The iso-butyl amide compound 29
also showed lower potency compared to compound 19. Attempts
to improve potency of the urea derivatives by introducing bulkier
functional groups gave mixed results. In the case of compounds
30 and 36, the potency was increased to sub-micromolar range,
while compounds 32 and 35 significantly lost potency with EC50
Preparation of the final compounds was accomplished by palla-
dium catalyzed amination of pyridine 7 with mono-substituted
piperazine 10 to provide analog 11. Removal of the Boc group in
11 with acids (Scheme 3), followed by further derivatization of
the piperidine with acyl chloride provided the desired final com-
pounds 12–39.
A variety of functional groups were introduced on the pipera-
zine. However, only alkylsulfonamide derivatives consistently gave
good potency (Table 1). Other functional groups, such as urea 12,
amide 13 and acetamide 14, all showed poor GPR119 agonism with
>10 lM. Data in Table 2 also clearly showed amide derivatives,
such as 29, 31 and 33–34, were weaker GPR119 receptor agonists.
In order to determine the optimal distance between the pyri-
dine ring and piperidine ring, the linker length was adjusted by
changing the number of methylene units (n = 0–2). As shown in
the table (Table 3), the linker length only had a modest effect on
GPR119 activity. Compound 37 (n = 0), where the oxygen was di-
rectly connected to the piperidine ring, had the lowest potency.
However, compounds with linker lengths of 1 and 2 methylenes
showed comparable potency.
EC50 >10
l
M. Compared to acetamide 14, 2-furanylamide 15
The pharmacokinetic profile of compound 19 was evaluated in
mouse (Table 4). The data showed compound 19 had low to med-
ium plasma clearance (CL = 15.7 mL/min/kg), short plasma half-life
showed improvement in potency. Arylsulfonamide derivatives
24–25 as well as N-alkylsulfamides 26–27 also showed lower po-
R
N
R
N
N
N
N
N
( )n
O
ii, iii
i
( )n
N
O
7
O
N
O
R'
11
12-39
Scheme 3. General procedure for the synthesis of the 2,5-disubstituted pyridines 12–39. Reagents: (i) 10, Pd(t-Bu3P)2, t-BuONa, toluene; (ii) 4 M HCl in 1,4-dioxane or TFA,
DCM; (iii) R0COCl, Et3N, DCM.

Y. Wu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2577–2581
2579
Table 1
In vitro human GPR119 agonisma data for analogs with different R groups
R
N
N
N
O
N
O
O
Compd
R
Human EC50
(lM)
M.R. (%)b
N
12
>10
23
O
N
O
13
14
15
>10
>10
11
<10
112
O
O
O
1.9
O
16
17
2.6
1.3
28
O
O
O
167
S
S
O
18
0.3
171
O
O
S
19
20
0.3
0.1
153
164
O
O
O
S
O
S
21
0.3
178
O
O
O
S
22
23
24
0.2
165
136
100
O
O
S
0.09
2.0
O
O
S
N
O
O
S
25
26
1.8
69
S
O
O
S
1.2
1.0
125
118
N
O
O
S
27
N
a
CHO:CRE reporter assay, see Ref. 17.
Percent of GPR119 receptor maximum response, see Ref. 18.
b

2580
Y. Wu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2577–2581
Table 2
In vitro human GPR119 agonisma data for analogs with different R0 groups
O
O
S
N
N
N
O
N
R'
b
Compd
R0
Human EC50
(lM)
M.R. (%)
O
N
19
0.3
153
45
O
O
O
O
O
O
28
29
30
31
32
1.0
1.6
186
75
N
0.8
2.8
175
16
N
F
>10
33
34
2.1
2.0
97
F
O
O
O
112
O
N
35
>10
41
67
O
N
36
0.9
O
a
CHO:CRE reporter assay, see Ref. 17.
Percent of GPR119 receptor maximum response, see Ref. 18.
b
Table 3
In vitro human GPR119 agonisma data for analogs with different linker lengths
Table 4
In vivo DMPK properties in mouse for compound 19
R
N
Compd Route Dose Cmax Tmax T1/2 AUC0–24
CL
VDSS
(mg/kg) (ng/mL) (h) (h) (ng h/mL) (ng/min/kg) (L/kg)
N
N
19
IV
PO
3
30
3077
2996
0.75 0.62 3132
0.25 0.40 2352
15.7
0.76
( )n
O
N
O
O
(T1/2 = 0.40 h) and high artificial membrane permeability (470 nm/
s). The measured fasted simulated intestinal fluid (FaSSIF at pH 6.5)
b
solubility of compound 19 (3.41 lg/mL) was comparable to those
Compd
R
n
Human EC50
(l
M)
M.R. (%)
of our corresponding biaryl compounds, which were also poorly
soluble. The low to medium clearance combined with high perme-
ability suggests low solubility be the culprit for low systemic expo-
sure (AUC0–24 = 2353 ng h/mL) and bioavailability (F ꢁ 8%) for this
compound.
37
17
38
19
39
EtSO2
EtSO2
EtSO2
n-PrSO2
n-PrSO2
0
1
2
1
2
2.1
1.3
1.2
0.3
0.7
93
167
69
153
95
a
In summary, we have synthesized a series of piperazinylpyri-
dine derivatives as GPR119 receptor agonists. Compounds with
CHO:CRE reporter assay, see Ref. 17.
Percent of GPR119 receptor maximum response, see Ref. 18.
b

Y. Wu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2577–2581
2581
14. Katamreddy, S. R.; Caldwell, D. R.; Heyer, D.; Samano, V.; Thompson, J. B.;
Carpenter, A. J.; Conlee, C. R.; Boros, E. E.; Thompson, B. D. WO2008008887,
2008.
15. Fang, J.; Tang, J.; Carpenter, A. J.; Peckham, G.; Conlee, C. R.; Du, K. S.;
Katamreddy, S. R. WO2008070692, 2008.
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Mutnick, D.; Nikulin, V.; Westcott-Baker, L. WO2009038974, 2009.
17. The assay consists of CHO-K1 6CRE-luciferase cells that stably express human
GPR119 receptor plated at 15,000 cells/well in Dulbecco’s Modified Eagle
Medium: Nutrient Mixture F12 (DMEM/F12), 5% fetal bovine serum (FBS),
alkylsulfonamide and isopropylcarbamate end groups showed
potent GPR119 receptor activity. However, the pharmacokinetic
profiles of compounds screened in this series, exemplified by com-
pound 19, were not optimal. Compound 19 possessed relatively
low exposure (AUC0–24) and a short half-life. Further efforts are
being focused on designing compounds with better pharmacoki-
netic profiles as GPR119 agonists for the treatment of type 2
diabetes.
2 mM
media is removed by aspiration and replaced with 20
-glutamine (no FBS) utilizing a Matrix Multidrop. Test compounds (20
then pipetted into the assay plate using a Packard Minitrak. The plates are then
incubated for 5 h at 37 °C. Under subdued light conditions, 15 L of a 1:1
L
-glutamine in black 384-well assay plates. On the following day, the
L of DMEM/F12, 2 mM
L) are
l
L
l
References and notes
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Endocrinology 2008, 149, 2038.
solution containing SteadyLite™ and Dulbecco’s Phosphate Buffered Saline
with 1 mM CaCl2 and 1 mM MgCl2 is added to the plates using a Matrix
Multidrop. Plates are then sealed with self-adhesive clear plate seals and the
amount of luciferase generated is quantified in
a Wallac Viewlux™.
Compounds are also tested in the same manner against cells without the
GPR119 receptor so as to check for false positives.
18. All compounds are referenced to
a small molecule GPR119 agonist for
evaluation of intrinsic efficacy (%max response) since this reporter assay is
not sensitive enough to demonstrate robust activity of putative endogenous
ligands (OEA, LPC, etc.). Our experience with the ꢁ3000 compounds made for
the program is that compounds with ꢁ80–200%max response are likely full
agonists. Compounds with consistent levels of receptor activation below 80%
may be partial agonists. The degree of variability in the assay accounts for the
large range considered as full agonists. The structure of our standard
5. Ning, Y.; O’Neill, K.; Lan, H.; Pang, L.; Shan, L. X.; Hawes, B. E.; Hedrick, J. A. Br. J.
Pharmacol. 2008, 155, 1056.
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compound 40, with an EC50 = 0.2 lM (max response = 100%), is shown below.
This compound is reported19 to have an EC50 = 0.13
lM in a cAMP assay.
N
N
N
N
N
N
H
N
NO2
9. Fyfe, M. C. T.; McCormack, J. G.; Overton, H. A.; Procter, M. J.; Reynet, C. Expert
Opin. Drug Discov. 2008, 3, 403.
10. Fyfe, M. C. T.; Overton, H. A.; Procter, M. J.; Reynet, C.; White, J. R. Annu. Rep.
Med. Chem. 2007, 42, 129.
S
N
40
11. Arena Pharmaceutical press release, Dec 15, 2008, San Diego, California.
12. Prosidion Pharmaceutical press release, Sep 3, 2008, Melville, NY.
13. Metabolex press release, Nov 12, 2008, Hayward, California.
19. Jones, R. M.; Graeme, S.; Fioravanti, B.; Pereira, G.; Calderon, I.; UY, J.; Duvvuri,
K.; Choi, J. S. K.; Xiong, Y.; Dave, V. WO2004065380, 2004.