Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity

Article abstract of DOI:10.1016/j.bmcl.2011.10.109

A series of γ-lactam prostaglandin E₁ analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K_i values: mEP2 = 9.3 nM, mEP4 = 0.41 nM). A structure-activity relationship study is presented.

Full text of DOI:10.1016/j.bmcl.2011.10.109

Bioorganic & Medicinal Chemistry Letters 22 (2012) 396–401
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity
⇑
Tohru Kambe , Toru Maruyama, Masayuki Nakano, Yoshihiko Nakai, Tadahiro Yoshida,
Naoki Matsunaga, Hiroji Oida, Akira Konaka, Takayuki Maruyama, Hisao Nakai, Masaaki Toda
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of
c
-lactam prostaglandin E1 analogs bearing a 16-phenyl moiety in the
x
-chain and aryl moiety
Received 12 September 2011
Revised 26 October 2011
Accepted 31 October 2011
Available online 7 November 2011
in the -chain were synthesized and biologically evaluated. Among the tested compounds,
a
c-lactam PGE
analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual
agonist with excellent subtype-selectivity (Ki values: mEP2 = 9.3 nM, mEP4 = 0.41 nM). A structure–
activity relationship study is presented.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Prostaglandin
Agonist
EP2 receptor
EP4 receptor
Receptors for prostaglandin E2 (PGE2) can be classified into four
subtypes, EP1, EP2, EP3 and EP4, each of which mediates different
effects in various tissues and cells.1 The EP4 receptor is distributed
in thymus, lung, heart, kidney, bone, womb and other organs, and
mediates an increase of the intracellular c-AMP concentration. Var-
ious biological actions of PGE2, including a cytoprotective action,
improvement of blood flow, regulation of inflammatory cytokine
production and bone resorption/formation, are thought to mediate
the EP4 subtype. A recent report suggests that an EP4 agonist is
capable of restoring bone mass and strength normally lost in rats
subjected to ovariectomy or immobilization.2 EP2 receptor agonists
have been shown to have an anabolic effect on bone formation in
various animal models.3 These findings led us to development of
a novel EP2/EP4 dual agonist which could prove to be a more ben-
eficial agent for the treatment of bone diseases such as osteoporosis
and fracture healing in humans. Several research groups have been
investigating the improvement of pharmacological properties of
PGE2.4–7 Efforts to improve the selectivity and chemical stability
of PGE2 have been focused mainly on two general chemical modifi-
high potency which showed potent inhibitory activity of LPS-in-
duced production of TNF-
in rats.8 Compound 2 was also reported
a
to be an EP4 receptor agonist.4 We focused on the activity profiles
of 2 because it displayed weak to moderate binding affinity
(Ki = 340 nM for mEP2, in-house data) for the EP2 subtype in addi-
tion to potent EP4 subtype affinity and moderate EP3 subtype
affinity (Table 1). Based on the information described above, more
detailed chemical modification of the benzoic acid moiety of 2 was
predicted to lead us to the discovery of a new structure which pos-
sesses a desirable activity profile as an EP2/EP4 dual agonist with
subtype-selectivity and high potency.
Herein we report on the discovery of a novel PGE analog of
structure 3 (Fig. 1) consisting of a structurally novel
ficial for EP2/EP4 receptor affinity, a -chain beneficial for EP4 sub-
type-selectivity and a -lactam ring as a replacement for the
chemically unstable -hydroxycyclopentanone.
a-chain bene-
x
c
c
Synthesis of test compounds listed in Tables 1–3 is described in
Schemes 1–6. Synthesis of 3 and 10–12 are presented in Scheme
1a. Ethanolysis of the S-acetyl group of 169 followed by S-arylation
with ethyl 2-bromothiazole-4-carboxylate and ethyl 2-bromothia-
zole-5-carboxylate resulted in 17 and 22, respectively. Deprotection
of the tert-butyldimethylsilyl (TBS) group with tetrabutylammo-
nium fluoride (TBAF) afforded 18a and 23, respectively. Compound
18a and 23 were transformed to the enones 20a–c and 24, respec-
tively by DMSO oxidation followed by Horner–Emmons reaction
using an optional phosphonate chosen from among 26a–c (Scheme
1c). Stereoselective reduction of 20a–c and 24 yielded 21a–c and 25,
respectively. Alkaline hydrolysis of 21a and 25 afforded 3 and 10,
respectively. Alkaline hydrolysis of 21b and 21c afforded 11 and
12, respectively.
cations: replacement of the a-alkenyl side chain with the phenyl-
ethyl group and replacement of the
c-hydroxycyclopentanone
moiety with 2-pyrrolidinone.
Our purpose was to develop PGE2 analogs with subtype-selec-
tivity and high potency for both receptor subtypes EP2 and EP4 be-
cause of their presumed therapeutic potential for the treatment of
bone diseases.
In our previous reports, we described 8-aza-5-thia PGE1 analog
1 (Fig. 1), an EP4 receptor agonist with high subtype-selectivity and
Synthesis of 13–15 is outlined in Scheme 1b. The ethyl ester 17
was transformed to the corresponding butyl ester 18b, which was
⇑
Corresponding author. Tel.: +81 75 961 1151; fax: +81 75 962 9314.
E-mail addresses: kanbe@ono.co.jp, t-kam@iris.dti.ne.jp (T. Kambe).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.109

T. Kambe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 396–401
397
CO2H
O
O
CO2H
S
N
N
CH3
CH3
OH
OH
1
2
CO2H
N
S
O
S
N
CH3
OH
3
Figure 1. Molecular design of c-lactam PGE analog 3 bearing the structurally novel x-chain beneficial for EP2/EP4 dual selectivity.
Table 1
Effect of the a-chain structure of the c-lactam PGE framework bearing the natural x-
chain on the activity profiles
Table 3
Activity profiles of
c-lactam PGE analogs bearing the 2-mercaptothiazole-4-carbox-
ylic acid
a
-chain and miscellaneous
x
-chain
O
X
CO2H
N
A
CO2H
N
O
N
CH3
S
S
OH
R
Compound
X
A
Binding assay (Ki, nM)
OH
mEP1
>104
mEP2
mEP3
mEP4
1.7
Compound
R
Binding assay (Ki, nM)
2
Bond
340
86
mEP1
3400
mEP2
3.0
mEP3
15
mEP4
0.5
4
5
PGE2
CH2
S
–(CH2)3–
–(CH2)3–
>104
>104
6.0
>104
2500
22
39
26
5.0
9.2
2.0
3.1
11
12
–(CH2)3CH3
*
>104
19
15
770
1.5
1.4
*
O
CF3
13
1900
1200
Table 2
Effect of the
methylphenyl)
O
*
*
a
-chain structure of the
c-lactam PGE framework bearing the 16-(3-
14
15
CH3
>104
>104
42
13
49
85
0.77
43
x
-chain on the activity profiles
O
R
N
CH3
OH
converted to the enones 20d–f by DMSO oxidation followed by
Horner–Emmons reaction using an optional phosphonate chosen
from among 26d–f (Scheme 1c). Alkaline hydrolysis of enones
20d–f afforded 13–15, respectively.
Compound
R
Binding assaya (Ki, nM)
mEP1
>104
mEP2
>104
mEP3
mEP4
To synthesize 6, we developed an alternative synthetic method
S
CO2H
1
6
5800
1.8
*
of 8-aza PGE analogs starting from N-Boc-D-glutamic acid as de-
CO2H
scribed in Scheme 2. Esterification of N-Boc-
D
-glutamic acid -ethyl
c
>104
410
>104
0.9
ester 27 with N-hydroxysuccinimide followed by hydride reduction
with lithium borohydride afforded 29, Swern oxidation of which
provided 30. The aldehyde 30 was converted to allyl alcohol 31
by Horner–Emmons reaction using 26a as a phosphonate followed
by stereoselective reduction of the formed enone carbonyl. Acidic
deprotection of 31 afforded 32. Reductive alkylation of 32 with an
appropriate aldehyde and sodium triacetoxyborohydride followed
by O-protection with TBS chloride resulted in the cyclized product
33. Palladium-catalyzed carbonyl insertion reaction of 33 followed
by treatment with methanol afforded a methyl ester 34, which was
*
*
S
7
8
CO2H
CO2H
>104
>104
127
240
1600
>104
0.6
35
N
N
N
S
*
*
*
*
O
S
S
N
CO2H
CO2H
CO2H
9
>104
>104
>104
84
>104
540
12
S
S
3
9.3
320
0.41
5.5
converted to
hydrolysis.
6 by acidic deprotection followed by alkaline
Synthesis of 7 is outlined in Scheme 3. N-Alkylation of 3510 with
methyl (5-bromopropyl)thiophene-2-carboxylate afforded 36.
10
>104

398
T. Kambe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 396–401
(a)
X
N
S
O
a or b
O
g
S
SAc
3 and 10-12
N
N
Y
OTBS
R1
X = CO2Et, Y = H
16
17
R1 = CH2OTBS
c
18a
R1 = CH2OH
R1 = CHO
d
19a
e
f
*
*
R1 =
R1 =
20a-c
21a-c
R2
R2
O
OH
X = H, Y = CO2Et
22 R1 = CH2OTBS
c
R1 = CH2OH
23
24
d,e
CH3
CH3
*
R1 =
O
f
25
*
R1 =
OH
(b)
O
N
O
O
CH3
h, i
g
S
N
17
S
13-15
R1
18b
19b
R1 = CH2OH
R1 = CHO
d
e
*
20d-f
21d-f
R1 =
R2
R2
f
O
R1 =
*
OH
(c)
CH3
CH3
R2 =
*
F
F
*
O
a
d
j
MeO
MeO
F
EtO2C
R2
P
O
R2
b
c
*
*
O
e
f
*
*
O
CH3
26
Scheme 1. Synthesis of 3, 10–15 and preparation of phosphonate 26. Reagents: (a) ethyl 2-bromothiazole-4-carboxylate, K2CO3, EtOH; (b) ethyl 2-bromothiazole-5-
carboxylate, K2CO3, EtOH; (c) TBAF, THF, 63–64% in two steps; (d) SO3-Py, i-Pr2NEt, DMSO, AcOEt; (e) 26a–c, NaH, THF; (f) (R)-Me-CBS, BH3-THF, THF, 35–56% in three steps;
(g) aq NaOH, DME, 80–93%; (h) K2CO3, n-BuOH; (i) TBAF, THF, 59% in two steps; (j) dimethyl methylphosphonate, n-BuLi, toluene, 75%.
Compound 36 was converted to 7 by the following sequential reac-
tions: (1) Swern oxidation; (2) Horner–Emmons reaction using 26a
as a phosphonate; (3) stereoselective reduction of the formed en-
one carbonyl; (4) alkaline hydrolysis.
Synthesis of 8 is described in Scheme 4. O-Protection of so-
dium 4-hydroxybutyrate with the tert-butyldiphenylsilyl (TBDPS)
group followed by peptide formation with the DL-serine methyl
ester afforded 37. Dehydration of 37 followed by oxidation re-
sulted in an oxazole 38, deprotection of which afforded 39.11
Reductive alkylation of 32 (Scheme 2) with an aldehyde, which
was prepared from 39 by the DMSO oxidation, followed by cycli-
zation afforded a c-lactam framework 40. Alkaline hydrolysis of
40 produced 8.
Compound 9 was synthesized as outlined in Scheme 5. 4,4-Dim-
ethoxybutyronitrile was converted to ethyl thiazole-4-carboxylate
41 by the following sequential reactions: (1) thioamide formation
with sodium hydrogen sulfide; (2) thiazole formation with ethyl
bromopyruvate; (3) acidic deprotection.12 Compound 41 was
transformed to 9 according to the same method as described
above.
Synthesis of 2 and 5 is described in Scheme 6. Compound 30
was converted to 42 by the usual method. Acidic deprotection of

T. Kambe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 396–401
399
X
O
ClH
NH2
j, k
f
NHBoc
R
g, h
N
CH3
6
EtO2C
CH3
EtO2C
OH
OTBS
32
R = CO H
27
28
2
33
34
X = Br
X = CO2Me
a
i
O
O
*
R =
N
O
b
O
OH
29
30
R =
R =
R =
*
*
c
CHO
d, e
CH3
*
31
OH
Scheme 2. Synthesis of 6. Reagents: (a) N-hydroxysuccinimide, SOCl2, pyridine, DMF, MeCN, 70%; (b) LiBH4, THF, 66%; (c) (COCl)2, i-Pr2NEt, DMSO, CH2Cl2; (d) 26a, NaH, THF;
(e) (R)-Me-CBS, BH3-THF, THF, 51% in three steps; (f) HCl in dioxane, EtOH, 100%; (g) 3-(4-bromophenyl)-propionaldehyde, NaBH(OAc)3, THF; (h) TBSCl, imidazole, DMF, 72%
in two steps; (i) CO gas, PdCl2(PPh3)2, 1,1-bis(diphenylphosphino)ferrocene, Et3N, DMSO, MeOH, 94%; (j) 2 N HCl, MeOH, DME; (k) 2 N NaOH, MeOH, DME, 76% in two steps.
O
O
a, b
S
CO2Me
NH
7
N
OTBS
OH
35
36
Scheme 3. Synthesis of 7. Reagents: (a) methyl 5-(3-bromopropyl)thiophene-2-carboxylate, NaH, DMF, 32%; (b) TBAF, THF, 100%.
H
N
a, b
c, d
e
N
CO2Me
OH
CO2Me
XO
TBDPSO
HO
CO2Na
O
O
38
39
X = TBDPS
X = H
37
CO2Me
CH3
O
N
O
h
f, g
N
8
OH
40
Scheme 4. Synthesis of 8. Reagents: (a) TBDPSCl, imidazole, DMF; (b) DL-serine methyl ester hydrochloride, EDC-HCl, Et3N, CH3CN, 32% in two steps; (c) diethylaminosulfur
trifluoride, K2CO3, CH2Cl2; (d) bromotrichloromethane, DBU, CH2Cl2, 54%; (e) TBAF, THF, 79%; (f) SO3-Py, i-Pr2NEt, DMSO, AcOEt; (g) 32, NaBH(OAc)3, THF, 74%; (h) aq NaOH,
MeOH, DME, 70%.
binding assay which was performed according to the method of
Kiriyama et al. with some modifications.9,15
OHC
a, b, c
OMe
d, e
To investigate the effect of the
a
-chain structure on the activity
-chain were
9
N
MeO
profiles, -chain analogs 2, 4 and 5 bearing a natural
a
x
CO2Et
compared for their subtype-selectivity and receptor affinity. Re-
sults are summarized in Table 1. Compound 4, which possesses
an N-heptanoic acid moiety, exhibited moderate binding affinity
and potent binding affinity for the EP3 and EP4 subtypes, respec-
tively while it did not exhibit receptor affinity for both the EP1
S
CN
41
Scheme 5. Synthesis of 9. Reagents: (a) NaSH, MgCl2–6H2O, DMF; (b) ethyl
bromopyruvate, DMF; (c) 2 N HCl, DME, 12% in three steps; (d) 32, NaBH(OAc)3,
THF, 60%; (e) 2 N NaOH, DME, MeOH, 66%.
and EP2 subtypes up to 10 lM. The corresponding 5-thia analog
5 showed moderate and highly potent receptor affinity for the
EP3 and EP4 subtypes, respectively while it showed very weak
receptor affinity for the EP2 subtype and no receptor affinity for
42 afforded 43. Reductive alkylation of 43 with 4-carbomethoxy
phenylacetaldehyde or an aldehyde 44 followed by alkaline hydro-
lysis afforded 5 and 2, respectively.13,14
Compounds listed in Tables 1–3 were evaluated for their bind-
ing affinity using membrane fractions of CHO cells expressing the
mouse EP-receptor. Ki values were determined by a competitive
the EP1 subtype up to 10 lM, respectively. According to our in-
house data, compound 2 tended to show increased affinity for
the EP2 receptor while retaining its potent EP4 receptor affinity
relative to the analog 4 while compound 2 showed moderate
receptor affinity for the EP3 subtype.

400
T. Kambe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 396–401
d, e
ClH
NH2
NHBoc
R
c
CH3
2 and 5
EtO2C
EtO2C
OH
43
R = CHO
R =
OHC
S
CO2Me
30
42
a,b
44
CH3
OH
Scheme 6. Synthesis of 2 and 5. Reagents: (a) 26b, NaH, THF; b) (R)-Me-CBS, BH3-THF, THF, 83% in two steps; (c) HCl in dioxane, EtOH, 100%; (d) 4-carbomethoxy
phenylacetaldehyde or 44, NaBH(OAc)3, THF, 50–55%; (e) 2N NaOH, MeOH, DME, 73–82%.
According to one of our previous reports, the 16-(3-methyl-
phenyl) moiety of 1 (Figure 1 and Table 2) was found to be one
additional contributions to the increase of EP2/EP4 dual affinities.
Thus, the excellent EP2/EP4 dual selectivity of 3 was thought to
be due to the overall effect expressed by the combination of all
of the above described factors.
of the optimized
x-chain moieties which helped to improve EP4
subtype-selectivity especially with reduction of EP3 receptor affin-
ity relative to 5 (Tables 1 and 2).8 Based on the results described
above, structural hybridization of 1 and 2 was thought to be a ra-
tional entry toward discovery of an EP2/EP4 dual agonist with high
subtype-selectivity and high potency. As shown in Table 2, replace-
ment of the 16-n-butyl moiety of 2 with the 16-(3-methylphenyl)
moiety afforded 6 with improved EP2/EP4 dual subtype-selectivity
due to the remarkable reduction of its EP3 receptor affinity.
Replacement of the 1,4-disubstituted phenylene moiety of 6 with
5-methylenethiophene-2-carboxylic acid, which was considered
to be a bioisostere of a 1,4-phenylene moiety, afforded 7 with equi-
potent EP4 receptor affinity and increased receptor affinities for
the EP2 and EP3 subtypes.16 Replacement of the 1,4-disubstituted
phenylene moiety of 6 with the 2-methylene-oxazole-4-carboxylic
acid and 2-methylene-thiazole-4-carboxylic acid moieties afforded
8 and 9 with a tendency of reduction of EP4 receptor affinity and
increase of EP2 receptor affinity, respectively. Replacement of the
1,4-disubstituted phenylene moiety of 6 with the 2-mercapto-
thiazole-4-carboxylic acid moiety afforded 3 with excellent EP2/
EP4 dual subtype-selectivity and potency although it showed in-
creased EP3 receptor affinity. Thus, replacement of the 2-methy-
lene of the thiazole moiety of 9 with a sulfur atom resulted in
increased affinities to all the three receptors, EP2, EP3 and EP4,
while retaining excellent EP2/EP4 dual subtype-selectivity.
It was of great interest that 2-mercaptothiazole-5-carboxylic
acid analog 10, which has similar activity profiles to the 1,4-disub-
stituted phenylene analog 6 due to the reduction of its affinities to
the three receptor subtypes EP2, EP3 and EP4, exhibited different
biological profiles from its isomer 3. The contrastive biological re-
sults of the two isomers 3 and 10 strongly suggested a different
mode of their interaction with the receptor subtypes EP2 and
EP4. According to our hypothesis, compound 3 was considered to
interact strongly with the EP4 receptor through the electrostatic
interaction of the carboxylic acid function. Another hydrogen bond
through the nitrogen atom of the thiazole moiety of 3 was consid-
ered to be beneficial for binding both the receptors EP2 and EP4.
The expected hydrogen bond of 10 with the receptors through
the nitrogen atom of the thiazole-5-carboxylic acid moiety, if
any, was considered not to be supportive as the one of 3 although
it was considered not to disturb such an interaction. The sulfur
atom of the 2-mercapto moiety of 3 was also considered to have
Optimization of the
was conducted by maintaining the
ward EP4 receptor selectivity as shown in Table 2. To reconfirm
the rationality of the 16-(3-methylphenyl) moiety as the most
a
-chain toward EP2/EP4 dual selectivity
-chain once optimized to-
x
optimized
x-chain structure for EP2/EP4 dual selectivity, further
chemical modification of the
taining the most optimized
x
-chain was carried out while main-
a-chain structure bearing 2-merca-
ptothiazole-4-carboxylic acid. Results are summarized in Table
3. Replacement of the 16-(3-methylphenyl) moiety of 3 with a
n-butyl moiety afforded 11 with loss of EP2/EP4 dual selectivity
mainly due to the increased EP3 receptor affinity. Removal of
the 3-methyl group of the 16-(3-methylphenyl) moiety of 3 affor-
ded 12 with maintenance of EP2/EP4 dual selectivity while reduc-
tion of the affinities for both the EP2 and EP4 receptors was
observed. Replacement of the 3-methyl moiety of the 16-(3-
methylphenyl) group of 3 with a 2,2,2-trifluoroethoxymethyl
moiety afforded 13 also with maintenance of the dual selectivity
while the receptor affinities for EP2, EP3 and EP4 were slightly re-
duced. Replacement of the 16-(3-methylphenyl) moiety of 3 with
the 2-methylfuran-5-yl moiety afforded 14 with 4.5-fold less po-
tent EP2 receptor affinity and 11-fold more potent EP3 receptor
affinity, respectively with maintenance of the potent EP4 receptor
affinity compared with compound 3. Replacement of the 16-(3-
methylphenyl) moiety of 3 with the aliphatic cyclopentyl moiety
afforded 15 while retaining EP2 receptor affinity, but possessing
6.4-fold more potent EP3 receptor affinity and 105-fold less po-
tent EP4 receptor affinity. Thus, the terminal 16-phenyl moiety,
which is required to reduce EP3 receptor affinity, was found to
be one of the important structural requirements for the EP2/EP4
dual selectivity.
In summary, a series of
c-lactam PGE analogs bearing a 16-phe-
nyl -chain were synthesized and evaluated. Among the tested
x
compounds,
group in its
c
x
-lactam PGE analog 3 bearing a 16-(3-methylphenyl)
-chain and 2-mercaptothiazole-4-carboxylic acid in
its
a-chain was discovered as the most optimized EP2/EP4 dual
agonist. Compound 3 showed both EP2 and EP4 agonist activity9
in rat CHO overexpressed cells with 90 and 0.79 nM (EC50s),
respectively. Full details including in vivo efficacy in rats will be re-
ported in due course.
some contribution to the fine tuning of the a-chain length and/or
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of 3 could be enhanced by its stronger acidity relative to 9. Also the
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