Discovery and optimization of arylsulfonyl 3-(pyridin-2-yloxy)anilines as novel GPR119 agonists

Article abstract of DOI:10.1016/j.bmcl.2013.04.014

We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy) anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties.

Full text of DOI:10.1016/j.bmcl.2013.04.014

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3609–3613
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and optimization of arylsulfonyl 3-(pyridin-2-yloxy)
anilines as novel GPR119 agonists
a
a
a
a
a
a
Jian (Ken) Zhang a, , An-Rong Li , Ming Yu , Yingcai Wang , Jiang Zhu , Frank Kayser , Julio C. Medina ,
Karen Siegler b, Marion Conn b, Bei Shan b, Mark P. Grillo c, John Eksterowicz a, Peter Coward b,
Jiwen (Jim) Liu a
⇑
a Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
b Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
c Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists
derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moi-
eties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved
pharmacokinetic (PK) properties.
Received 1 March 2013
Accepted 5 April 2013
Available online 15 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
GPR119 agonist
Type 2 diabetes
Metabolic stability
SAR optimization
Type 2 diabetes mellitus is a critical health care issue that affects
more than 25 million people in the U.S. and 280 million world-
wide.1 Although many treatment options are available, especially
during the early stages of the disease, many patients are still unable
to achieve their target plasma glucose level. In addition, hypoglyce-
mia remains a serious potential side effect of several anti-diabetic
agents including insulin and the sulfonylureas, drugs which in-
crease insulin secretion independent of the prevailing plasma glu-
cose concentration. New oral agents that increase endogenous
insulin secretion in a glucose-dependent manner have the potential
to deliver robust efficacy with much lower risk of hypoglycemia.
GPR119 is a G protein-coupled receptor predominantly ex-
pressed in pancreatic islet b-cells and incretin releasing cells in
the gastrointestinal tract. Phospholipids and lipid amides, such as
oleoylethanolamide (OEA), have been identified as endogenously-
occurring GPR119 agonists2,3 and several reports have described
synthetic agonists.4–6 Activation of GPR119 results in elevation of
intracellular cAMP both in a pancreatic b-cell line and in transfec-
ted cells. Physiologically, activation of GPR119 increases glucose-
dependent insulin secretion from the pancreas and incretin secre-
tion from the gut. Several synthetic GPR119 agonists have been
evaluated in clinical studies, but it is still too early to know
whether activation of this pathway will result in meaningful
antidiabetic efficacy in humans. In this letter, we describe a medic-
inal chemistry study of a high-throughput screen (HTS) hit, com-
pound 1, which led to the identification of the arylsulfonyl 3-
(pyridin-2-yloxy)aniline compound 34 as a potent and efficacious
GPR119 agonist with improved PK properties.
Compound 1 was identified as a GPR119 agonist in a HTS of our
compound library collection using a cAMP assay. The EC50 of 1 was
310 nM, with a maximal response (max %) of 105% compared to the
previously reported compound 2 (Fig. 1).7 Compound 1 had good
selectivity against more than 19 related in-house targets. However,
the compound was rapidly metabolized in both human and mouse
liver microsomes (turnover = 72% and 100%, respectively, after
30 min incubation at 37 °C). Metabolite identification studies indi-
cated that various oxidations occurred at the three methyl groups
and also on the central electron-rich phenyl rings. We therefore
aimed to improve the stability of the molecule by focusing on
replacement of the methyl groups.
Our first step in the optimization was to determine the optimal
substitution pattern for the middle aryl ring. The analogues with
the ortho- (3) and para- (4) substitution pattern of the middle aryl
ring (Fig. 2) exhibited no activity in the GPR119 cAMP assay. The
results indicated that the 1,3-substitution is critical for the agonist
activity, and therefore, the subsequent optimization used the meta-
isomer as the core of the molecules.
To further investigate the relationship between 1 and 2 and to
leverage the knowledge from the resulting inactivity of 3 and 4, a
⇑
Corresponding author.
E-mail address: jian@amgen.com (Jian (Ken) Zhang).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.04.014

3610
Jian (Ken) Zhang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3609–3613
Table 1
O
SAR of the sulfonyl phenyl ring
N
O
Me
N
O
N
4
NC
O
Me
N
R
O
Me
NC
O
N
3
2
S
1
N
O
N
Me
O
H
N
S
O
N
Me
H
Compounds
R
h-GPR119cAMP EC50
efficacya,b,c (%)
(lM) /
O
S
1
2
1
5
6
7
8
9
10
11
12
13
4-Me
4-H
0.31/105
8.4/112
0.66/85
0.81/26
0.27/118
0.38/105
0.96/110
1.60/91
0.38/46
0.44/111
O
4-Et
4-iPr
4-Cl
Figure 1. Structure of screening hit 1 and reference compound 2.
4-F
4-CN
4-NO2
4-OCF3
4-OMe
Me
Me
Me
N
NC
O
H
N
NC
O
Me
S
N
Me
O
O
a
b
c
Me
NH
Values are means of two or more experiments.
See Ref. 7 for assay protocol.
Efficacy relative to compound 2.
S
O
O
3
4
Figure 2. Structure of compounds 3 and 4.
We then focused on the replacement of the methyl group on the
sulfonyl phenyl ring. Thus, the para-position methyl group on this
phenyl ring was systematically replaced with various alkyl, alk-
oxyl, halo and electron-withdrawing groups such as NO2 and CN.
The analogues were synthesized according to the chemistry as
illustrated in Scheme 1. The N-(3-hydroxyphenyl)-benzene-sulfon-
amides, the intermediates A, were obtained by reaction of the cor-
responding substituted benzenesulfonyl chloride with 3-
aminophenol in presence of pyridine. Subsequent treatment of 2-
chloronicotinonitrile with intermediates A offered the correspond-
ing products 5–13 in 35–70% yields. The assay results indicated
that the para-substitution was the key pharmacophore required
for the activity (Table 1). Removing the methyl group led to com-
pound 5 (R = H), which displayed very weak potency. Increasing
the size of the alkyl groups (R = 4-Et, 4-iPr) slightly decreased the
potency. Chlorine (Cl) and small alkoxyl groups could be added
while maintaining potency. Moving the methyl or Cl group from
para- to other positions on the phenyl ring (m- and o-) did not im-
prove the potency (data not shown). Overall, the modifications in
this phenyl ring did not significantly improve the potency. How-
ever, the addition of Cl in compound 8 was tolerated and in subse-
quent experiments shown to marginally improve human liver
microsome stability (HLM turnover = 66% vs 72% for 1). Therefore
further optimization was conducted using 4-chloro substituted
phenyl group as left hand side.
Figure 3. Modeling structure of compounds 1 and 2.
pharmacophore model was generated for compound 1.8 The result-
ing model is shown on the left in Figure 3 and illustrates a low en-
ergy conformation with four features of interest, two acceptors and
two aromatic rings. Illustrated to the right is the alignment of a low
energy conformation of compound 2 to compound 1 based on the
pharmacophore. The alignment shows overlap between the central
aryl ring of 1 and the bicyclic core of 2 and also shows alignment
between the phenyl rings on the left hand side of the molecules.
There is also overlay with the ether acceptors from both com-
pounds and the sulfonamide oxygen atoms of 1 with a nitrogen
atom from the bicyclic core of 2. However, with this alignment
there is no significant overlap with the right hand side of the com-
pounds. This was improved with subsequent optimization.
Next we turned our attention to the metabolic stability issue of
the two methyl groups on the pyridine by replacing them with
R
R
O
a
S
O
+
N
OH
H2N
OH
H
SO2Cl
A
Me
Me
N
4
3
NC
O
NC
Cl
b
R
O
S
A
+
1
N
H
N
Me
Me
2
O
5-13
Scheme 1. Synthesis of compounds 5–13. Reagents and conditions: (a) pyridine, rt, overnight, 25-80%; (b) DMF, 100 °C, overnight, 35-70%.

Jian (Ken) Zhang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3609–3613
3611
Table 2
SAR of the pyridine ring
stability significantly and its microsomal turnover in HLM was
13%. In rats, the clearance of this compound was 0.19 L/h/kg
(0.5 mg/kg, iv administration). This result demonstrated that the
stability issue could be addressed by modification of these methyl
groups. However, the potency for this compound declined eight-
fold compared to compound 8 which limited its further utility.
Additional optimization around the pyridine moiety led to
improvements of potency by introducing an ester group at R2, Ta-
ble 2. Compound 17 significantly improved the potency and was
the first compound that achieved an EC50 in the double-digit nM
range in the cAMP assay (EC50 = 13 nM). Similar results were also
observed with other ester compounds. The potency improvement
seemed to result from the direct interaction of the ester group with
the target, as the acid derivative, 20, was not able to maintain the
activity. Smaller groups at R1 gave improved potency, as shown by
compounds 17–19 (Table 2). Next, considering the potential meta-
bolic liability of the ester group, we replaced the ester with isoster-
ic groups such as amides and heterocycles.9 As shown in Table 2,
the amides of primary amines (21 and 22) were more potent than
the amides of secondary amines (23 and 24).
Our next goal was to further simplify the molecular structure by
removing the cyano group.10 Compared with 17, compound 25
showed slightly decreased potency; however, replacing the methyl
group with chlorine (compound 26) retained the potency of 17 (Ta-
ble 3). Converting the ester into an amide in this series did not im-
prove the potency (28, Table 3). However, replacing the ester
group with 5-membered heterocycles resulted in a compound with
balanced potency and pharmacokinetic profile. The heterocycles 29
to 34 were synthesized according to the procedures outlined in
Scheme 2. Treatment of acid chloride with 1H-1,2,3-triazole in
tetramethylenesulfone under heating condition offered oxazole
29.11 The carbothioamides C were prepared from the acid B through
R2
N
Cl
NC
O
O
S
R1
N
O
H
Compounds
R1
R2
h-GPR119cAMP EC50
efficacya,b,c (%)
(lM) /
8
Me
Me
CF3
cPr
Me
cPr
tBu
Me
cPr
Me
Me
Me
Me
H
0.27/118
1.71/125
2.12/102
2.06/103
0.013/105
0.13/115
4.0/101
2.74/130
0.031/97
0.35/108
2.95/121
0.61/122
14
15
16
17
18
19
20
21
22
23
24
H
CF3
CO2Et
CO2Et
CO2Et
CO2H
CON(H)cPr
CON(H)tBu
CONMe2
CONEt2
a
b
c
Values are means of two or more experiments.
See Ref. 7 for assay protocol.
Efficacy relative to compound 2.
more metabolically stable groups while maintaining or improving
the potency (Table 2). The compounds with other alkyl and hydro-
gen group were tolerated but only with decreased potency. For
example, compound 14 with R2 = H showed a sixfold decrease in
potency as compared with the parent methyl compound 8. As ex-
pected, replacing the methyl groups with metabolically stable
groups helped the compounds to further improve stability. As an
example, compound 16, with R1 = c-Pr and R2 = CF3, increased
Table 3
SAR of the pyridine ring
R2
Cl
O
S
N
O
N
R1
O
H
Compounds
R1
R2
h-GPR119cAMP EC50
efficacya,b,c (%)
(lM) /
25
26
27
28
Me
Cl
H
CO2Et
CO2Et
CO2Et
0.05/80
0.016/92
0.16/78
0.45/99
Cl
CON(H)cPr
N
O
29
30
31
Cl
Cl
Cl
0.091/94
0.068/88
0.089/80
N
S
N
S
N
32
Cl
0.30/98
N
N
H
N
33
34
Cl
1.06/87
N
O
N
N
Cl
0.024/85
N
a
b
c
Values are means of two or more experiments.
See Ref. 7 for assay protocol.
Efficacy relative to compound 2.

3612
Jian (Ken) Zhang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3609–3613
N
O
O
O
N
R
Cl
b
Cl
a
O
N
A
+
O
S
O
O
R = Cl
N
O
N
R
S
O
Cl
H
N
O
N
Cl
(R = 4-Cl)
H
O
34
c
R = Cl
H
N
O
O
OH
O
N
Cl
Cl
e
Cl
O
d
O
O
S
O
S
O
N
H
O
N
Cl
S
N
O
N
Cl
N
H
O
N
Cl
H
O
28
B
29
f
N
N
N
R
S
NHR'
Cl
Cl
S
N
Cl
h
O
g
Cl
O
S
O
N
H
O
N
Cl
S
O
O
N
H
O
N
S
O
32
N
O
N
Cl
C
H
30
R = H,
R = Et, 31
i
N
N
HN
Cl
O
S
N
O
N
Cl
O
H
33
Scheme 2. Synthesis of compounds 29–34. Reagents and conditions: (a) Cs2CO3, DMSO, 80 °C, overnight, 32%; (b) NaH, N0-hydroxyisobutyrimidamide, THF, reflux, overnight,
21%. (c) LiOH, THF–MeOH, rt, 5 h, 92%; (d) (i) cat. DMF, oxalyl chloride, THF, rt, 0.5 h; (ii) 1H-1,2,3-triazole, K2CO3, tetramethylenesulfone, 140 °C, overnight; (e) (i) cat. DMF,
oxalyl chloride, THF, rt, 0.5 h; (ii) cyclopropanamine, triethyl amine, 80%. (f) R0 = H, (i) cat. DMF, oxalyl chloride, THF, rt, 0.5 h; (ii) NH4OH; 97% (iii) Lawesson’s reagent, THF,
reflux, 2 h; 58%; R0 = Et, (i) cat. DMF, oxalyl chloride, THF, rt, 0.5 h; (ii) EtNH2; 91% (iii) Lawesson’s reagent, THF, reflux, 2 h; 68%; (g) R = H, bromoacetaldehyde dimethyl acetal,
DMF, rt 2 h; 21%; R = Et, 1-bromo-2-butanone, EtOH, 90 °C, 3 h; 36%; (h) formic acid hydrazide, Hg(OAc)2, 1,4-dioxane, reflux, overnight; (i) propionohydrazide, Hg(OAc)2, 1,4-
dioxane, reflux, 45 min, 5%.
the formation of the amides and subsequent treatment with the
Acknowledgments
Lawesson’s reagent. The thiazoles 30 and 31 were obtained from
the reaction of these thioamides C with a-bromo substituted alde-
We thank Alan Hao, Steve Rubenstein, Christine Hedberg and Ji
Ma for providing reference compound and their initial support and
efforts of this work.
hyde or ketone. The triazole compounds 32 and 33 were synthesized
by reaction of the corresponding thioamides with hydrazides in
presence of Hg(OAc)2 in dioxane. Reaction of ester with N0-hydrox-
yisobutyrimidamide in presence of NaH under THF reflux condition
gave oxadiazole compound 34. As indicated in Table 3, most of the
heterocycles were tolerated well. The isopropyl-1,2,4-oxadiazol-5-
ylpyridine compound 34 was the most potent heterocycle analogue
that achieved the similar potency as the esters compounds 17 and
26. In addition, the pharmacokinetic properties of this compound
were evaluated; this compound displayed a moderate clearance of
1.8 L/h/kg in rat.
In summary, we have explored a GPR119 agonist screening
hit to improve its stability and potency, which led to the discov-
ery of compound 34, a 24 nM agonist with an improved pharma-
cokinetic profile. The metabolic instability of the hit was
resolved by replacing methyl groups with appropriate metaboli-
cally stable substitutions. The potency was dramatically im-
proved by introducing ester and its isosteres. Subsequent
replacement of the ester with small heterocycles led to the dis-
covery of an oxadiazole compound with well-balanced potency
and PK properties.
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