Structure-activity relationship studies of novel 3-oxazolidinedione-6- naphthyl-2-pyridinones as potent and orally bioavailable EP3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2011.03.107

Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring,

Full text of DOI:10.1016/j.bmcl.2011.03.107

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2806–2811
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationship studies of novel 3-oxazolidinedione-6-naphthyl-
2-pyridinones as potent and orally bioavailable EP3 receptor antagonists
⇑
⇑
Ángel I. Morales-Ramos , Yue H. Li, Mark Hilfiker , John S. Mecom, Patrick Eidam, Dongchuan Shi,
Pei-San Tseng, Carl Brooks, David Zhang, Ning Wang, Jon-Paul Jaworski, Dwight Morrow, Harvey Fries,
⇑
Richard Edwards, Jian Jin
GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput
screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione
moiety, a-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the cen-
tral pyridinone core led to the discovery of potent EP3 receptor antagonists such as compound 29 which
possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and
DMPK properties of representative compounds are discussed.
Received 6 February 2011
Revised 25 March 2011
Accepted 29 March 2011
Available online 5 April 2011
Keywords:
EP3 receptor
Ó 2011 Elsevier Ltd. All rights reserved.
Novel, potent, selective, and orally active
antagonists
3-Oxazolidinedione-6-aryl-pyridinones
Prostaglandins (PGs), are produced from the cyclooxygenase-
mediated metabolism of arachidonic acid. They are a subclass of
prostanoids involved in many physiological and pathophysiologi-
cal processes.1,2 Five prostanoid family receptors are known: DP,
EP, FP, IP and TP. Prostaglandin E2 (PGE2) is the natural ligand
attributed to the activation of subtype receptors EP1, EP2, EP3 and
EP4.3 Studies on the EP3 receptor have shown that it plays a key
role in platelet aggregation and thrombosis,4,5 fever generation,6
hyperalgesia,7 duodenal bicarbonate secretion and mucosal integ-
rity.8 Recently, PGE2 and the EP3 receptor have been linked to over-
active bladder (OAB).9–12 The potential of selectively inhibiting the
EP3 receptor to treat various inflammatory conditions has
prompted us to pursue a potent and selective EP3 antagonist.
O
O
O
H
HN
O
N
H
1, Human EP3 fpKi = 6.7
Figure 1.
ity in several OAB animal models.27 Herein, we describe our detailed
SAR studies and optimization of multiple regions of this chemical
series that resulted in the identification of lead compounds such as
compound 29. We began the hit to lead optimization with the
high-throughput screening (HTS) hit, compound 1 (Fig. 1), which
had a functional pKi (fpKi)28 of 6.7 in a human EP3 fluorometric imag-
ing plate reader (FLIPR) assay.27,29
A
number of small molecule EP3 antagonists have been
reported.3,13–26 Most recently, we have reported the discovery of
3-oxazolidinedione-6-aryl-pyridinones as potent, selective, and or-
ally active EP3 antagonists, which demonstrated robust in vivo activ-
The a-substitution of the oxazolidinedione moiety was investi-
⇑
Corresponding authors at present addresses: Vitae Pharmaceuticals, 502 West
gated first. A general synthetic approach for these analogs is shown
in Scheme 1.30 Commercially available 2-bromo-6-methoxypyri-
dine (2) was coupled with 2-naphthalenylboronic acid, under Su-
zuki cross-coupling conditions yielding the biaryl compound 3.
The ortho-lithiation adduct of 3 was quenched with diethyl oxalate
yielding the a-ketoester 4 as the major regioisomer with a regiose-
lectivity of 20:1. Treatment of 4 with different Grignard reagents
provided alcohols 5. The oxazolidinedione ring was efficiently
Center Office Drive, Fort Washington, PA 19034, USA. Tel.: +1 215 461 2068; fax: +1
215 461 2006 (Á.I.M.). Medicinal Chemistry, Heart Failure DPU, Metabolic Pathways
and Cardiovascular Therapeutic Area, GlaxoSmithKline, 709 Swedeland Road, PO
Box 1539, King of Prussia, PA 19406-0939, USA. Tel.: +1 610 270 4472; fax: +1 610
270 6609 (M.H.). Center for Integrative Chemical Biology & Drug Discovery, Division
of Medicinal Chemistry & Natural Products, Eshelman School of Pharmacy, The
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7363, USA. Tel.:
+1 919 843 8459; fax: +1 919 843 8465 (J.J.).
E-mail addresses: amramos@vitaerx.com (Á.I. Morales-Ramos), mark.a.hilfi-
ker@gsk.com (M. Hilfiker), jianjin@unc.edu (J. Jin).
formed by the acylation of the
a-hydroxyesters 5 with trichloro-
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.107

Á. I. Morales-Ramos et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2806–2811
2807
O
EtO
a
b
O
N
O
O
N
Br
O
N
2
3
4
O
HO
R1
O
O
R1
EtO
HN
c
d, e
O
O
O
N
N
H
5
6
Introduction of R2
O
O
N
O
O
O
O
R1
R1
R2
R2
N
f
e
5
O
O
N
N
H
7
8
Scheme 1. Synthesis of compounds 6 and 8. Reagents and conditions: (a) 2-naphthalenylboronic acid, PXPd2, K2CO3, MeOH, 60 °C; (b) t-BuLi, THF, À78 °C or MeLi, HN(i-Pr)2
cat. THF, À78 °C, then added to (CO2Et)2, THF, À78 °C; (c) R1-MgCl or R1-MgBr, THF, À78 °C; (d) (i) Cl3CCONCO, DCM, rt, (ii) 1 M K2CO3 (aq), reflux; (e) TMSCl, NaI, CH3CN, rt or
TMSI, CH3CN, rt; (f) R2NCO, NaH, THF, rt.
acetyl isocyanate followed by concominant cyclization upon treat-
ment with aqueous potassium carbonate at reflux.31 Demethyla-
tion of the 2-methoxypyridines provided 6-arylpyridinones 6. To
introduce a substituent in the oxazolidinedione nitrogen, the cor-
responding alkyl isocyanates were reacted with the intermediate
5 to directly afford the cyclization adducts 7 and, upon demethyl-
ation arylpyridinones 8 were obtained.
results as methyl analog 6a, while trifluoromethyl analog 6h was
near 10-fold less potent than 6a. Interestingly, 4-substituted tetra-
hydropyran 6i was near 30-fold less potent than its cyclohexyl
analog 6e. Substitution in the oxazolidinedione nitrogen (8a–b)
proved to be unfavorable, showing a decrease in potency when
increasing the bulkiness of the substituent.
After investigating the
a-substituent of the oxazolidinedione
The results for
are illustrated in Table 1. The replacement of the
a
-substituted oxazolidinediones 6a–i and 8a–b
moiety, we turned our attention to exploring other heterocyclic
rings at the C3 of the pyridine ring. The syntheses of the studied
analogs are shown in Scheme 2. Commercially available 2-chloro-
6-methoxypyridine 9 was ortho-lithiated, quenched with an acetyl
Weinreb amide and coupled with 2-naphthalenylboronic acid yield-
ing the methyl ketone 10 as the major regioisomer again with 20:1
regioselectivity. This ketone was exposed to ammonium carbonate
and potassium cyanide providing the hydantoin pyridine intermedi-
ate which upon demethylation afforded the hydantoin pyridinone
11. The cyclic urea analog 13 was obtained by chemoselective reduc-
tion of hydantoin 12 followed by demethylation. To obtain the oxa-
zolidinone 15, the methyl ketone 10 was treated with TMSCN and
the corresponding product was reduced to the amino alcohol 14.
Treatment of the amino alcohol with phosgene produced the oxazo-
lidinone pyridine adduct which was subsequently demethylated to
afford 15.
Our findings on oxazolidinedione replacements 11, 13 and 15
are shown in Table 2. Hydantoin 11 showed a 15-fold decrease in
potency compared with oxazolidinedione 6a. Interestingly, cyclic
urea 13 and oxazolidinone 15 were only slightly less potent com-
pared to oxazolidinedione 6a. Since the oxazolidinedione moiety
was the most potent left-hand side group identified to date, we
have held it constant during subsequent SAR studies.
a-hydrogen (1)
by a methyl group (6a) provided 10-fold boost in potency. The
introduction of an isopropyl group (6b) further increased potency
(fpKi = 8.0). While its cyclopropyl analog 6c was less potent, the
less strained analogs such as 6d and 6e containing a respective
cyclopentyl and cyclohexyl ring showed similar potency as 6b.
Phenyl and benzyl analogs 6f and 6g, respectively, showed similar
Table 1
SAR of
a
-substituted oxazolidinediones 6a–i and alkyl analogs 8a–b
O
O
R1
R2
N
O
O
N
H
Compounds
R1
R2
hEP3 FLIPR fpKi
1
H
CH3
i-Pr
c-Pr
c-Pentyl
c-Hexyl
Ph
H
H
H
H
H
H
H
H
H
H
CH3
i-Pr
6.7
7.7
8.0
7.3
8.1
8.1
7.5
7.8
6.9
6.7
6.3
5.8
6a
6b
6c
6d
6e
6f
6g
6h
6i
The 2-pyridinone core was investigated next. Synthesis of ana-
logs 18, 19, 22, 25 and 26 are outlined in Scheme 3. Compound 17
was prepared by selective lithium halogen exchange and quenched
with ethyl pyruvate of bromoanisole 16 followed by the oxazolid-
inedione ring formation. Suzuki cross-coupling of chloroanisole 17
yielded the methoxyphenyl analog 18 which upon treatment with
boron tribromide afforded the phenol 19. Selective lithium halogen
exchange of 5-bromo-2-chloropyridine 20 followed by quenching
Bn
CF3
4-Tetrahydropyran
CH3
CH3
8a
8b

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Á. I. Morales-Ramos et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2806–2811
Hydantoin
O
O
O
NH
CH3
HN
H3C
c, d
a, b
O
N
Cl
O
N
O
N
H
9
10
11
Cyclic Urea
O
O
NH
NH
O
CH3
CH3
HN
HN
e, d
O
O
N
N
H
12
13
Cyclic Carbamate
O
HO
O
CH3
N
CH3
H2N
HN
f, g
h, d
10
O
O
N
H
14
15
Scheme 2. Synthesis of compounds 11, 13 and 15. Reagents and conditions: (a) t-BuLi, THF, À78 °C, then added to CH3CON(CH3)OMe, THF, À78 °C; (b) 2-naphthalenylboronic
acid, PXPd2, K2CO3, MeOH, 100 °C,
0 °C–rt; (h) COCl2, NEt3, Et2O.
lW, 5 min.; (c) (NH4)2CO3, KCN, EtOH/H2O (1:1), 75 °C; (d) TMSCl, NaI, CH3CN, rt (e) AlCl3, LAH, THF, 0 °C–rt; (f) TMSCN, NEt3 (g) LAH, Et2O,
Table 2
Table 3
SAR of oxazolidinedione replacements 11, 13 and 15
Pyridinone core SAR studies
Compounds
hEP3 FLIPR fpKi
O
X
18
19
22
25
26
5.5
5.9
<4.6
6.1
<4.6
CH3
HN
Y
O
N
H
N-methylation of the 2-pyridinone nitrogen (26) resulted in com-
plete lost of its activity against the receptor. Therefore, it can be
concluded that the 2-pyridinone moiety is the optimal core for this
chemical series.
We next explored the 5-substituent at the 2-pyridinone ring.
Synthesis of compounds 28a–b, 29, 30, and 33 is depicted in
Scheme 4. The intermediate 7b was halogenated by either NCS or
NBS and, after subsequent demethylation, analogs 28a–b were ob-
tained. Methyl and phenyl analogs 29 and 30, respectively, were
obtained by the corresponding Negishi or Suzuki-Miyaura cross-
couplings. The trifluoromethyl analog 33 was obtained by the
chemistry previously discussed using compound 31 as the key
starting material.27
Table 4 illustrates the SAR trends on C5 substitution at the 2-
pyridinone ring. Introduction of a halo group such as chloro
(28a) and bromo (28b) at C5 displayed over 5-fold potency de-
crease. In addition, a phenyl or trifluoromethyl group at C5, com-
pounds 30 and 33 respectively, had detrimental effects on hEP3
potency. On the other hand, 5-methyl analog 29 was equal to or
slightly more potent than the parent compound 6b. We next eval-
uated compounds 28a and 29 in rat PK studies and were pleased to
find that both compounds had outstanding rat PK properties
including very low clearance, long half life, and excellent oral bio-
availability (Table 4).32 Despite being a sensitive area in respect of
hEP3 potency, substitution at the C5 of the 2-pyridinone ring of-
fered an improvement in an already good PK profile by further low-
ering the clearance and increasing the half life.
Compounds
X
Y
hEP3 FLIPR fpKi
6a
11
13
15
O
O
O
H2
H2
7.7
6.5
7.4
7.1
NH
NH
O
with diethyl oxalate produced the a-ketoester intermediate, which
was treated with i-PrMgCl. The resulting hydroxyester was cy-
clized to afford the oxazolidinedione 21. Palladium catalyzed
cross-coupling of 21 with 2-naphthalenylboronic acid produced
the pyridine analog 22. The synthesis of the 4-pyridinone 25
started from the Suzuki cross-coupling of chloropyridine 23 fol-
lowed by bromination to yield the intermediate 24 as the only iso-
mer observed. The oxazolidinedione ring was installed as
previously described and subsequent demethylation afforded 25.
N-methyl pyridinone 26 was prepared by methylation of the corre-
sponding pyridinone followed by deprotection of the 4-methoxy-
benzyl group.
Replacement of the 2-pyridinone core with the methoxy phenyl
group (18) resulted in a detrimental 100-fold potency loss com-
pared with the parent compound 6a (Table 3). A similar result
was observed with the phenol analog 19. The pyridine core such
as in compound 22 abolished the antagonist activity versus the
EP3 receptor. Interestingly, 4-pyridinone analog 25 was close to
100-fold less potent compared to its parent compound 6b. Finally,

Á. I. Morales-Ramos et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2806–2811
2809
Phenol and Methoxyphenyl cores
O
HN
O
O
Br
O
CH3
CH3
HN
a, b
c
O
Cl
O
O
O
R
O
Cl
16
17
18, R = CH3
19, R = H
d
Pyridine core
O
O
O
Br
O
HN
e, f,
c
HN
b
O
N
Cl
O
N
N
Cl
20
21
22
4-Pyridinone core
O
OMe
O
O
OMe
Br
HN
c, g
h, b,
i
O
N
N
H
N
Cl
23
24
25
N-Methyl-2-pyridinone core
O
O
CH3
j, k,
l, m
HN
5a
O
R = CH3
O
N
CH3
26
Scheme 3. Synthesis of compounds 18, 19, 22, 25 and 26. Reagents and conditions: (a) n-BuLi, THF, À78 °C, then added to ethyl pyruvate, THF, -78 °C; b) i. Cl3CCONCO, DCM,
r.t., ii. 1M K2CO3 (aq), reflux; (c) 2-naphthalenylboronic acid, Pd(OAc)2, PCy3, 1,4-Dioxane/H2O (6:1), K2CO3, 150 °C,
l
W, 20 min.; (d) BBr3, DCM, rt; (e) n-BuLi, THF, À78 °C,
then added to (CO2Et)2, THF, À78 °C; (f) i-PrMgCl, THF, À78 °C–0 °C; (g) NBS, TFA (cat), CH3CN, 55 °C; (h) n-BuLi, THF, À78 °C, then added to ethyl 3-methyl-2-oxobutyrate,
THF, À78 °C; (i) NaSMe, DMF, 80 °C; (j) PMBNCO, DBU, DCM, rt; (k) TMSCl, NaI, CH3CN, rt; (l) NaH, MeI, DMF, 80 °C; (m) CAN, DCM, rt.
Table 4
SAR and rat PK properties of 5-substituted 2-pyridinones
O
O
HN
R
O
O
N
H
Compds
R
hEP3 FLIPR fpKi
Rat PKa
DNAUC_PO (
Cl (mL/min/kg)
T1/2 (h)
lg.h/mL/mg/kg)
Oral F (%)
6b
H
Cl
Br
CH3
Ph
CF3
8.0
7.3
7.4
8.2
5.6
6.2
5.1
1.2
n/a
1.4
n/a
n/a
3.5
5.3
4.4
12.9
100
86
28a
28b
29
30
33
6.6
13.5
100
a
DMPK properties are averaged values (n = 3) from an i.v./p.o. study in Sprague–Dawley rats dosed at 2 mg/kg (p.o.) and 1 mg/kg (i.v.).
The stereochemistry of the stereogenic carbon present in the
oxazolidinedione moiety was also investigated. The enantiomers
of compound 6b were separated by chiral high-performance liquid
chromatography (HPLC) yielding 34 and 35.33 The absolute config-
uration of the enantiomers was established by vibrational circular
dichroism (VCD). As shown in Table 5, the S enantiomer (35) was

2810
Á. I. Morales-Ramos et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2806–2811
O
O
O
O
O
O
HN
HN
R
R
a
b
7b
O
O
R1 = i-Pr
N
N
H
R
2 = H
27a, R = Br
27b, R = Cl
28a, R = Br
28b, R = Cl
O
O
O
O
HN
HN
Ph
CH3
d, b
c, b
27a
27a
O
O
O
N
H
O
N
H
29
30
O
O
O
CF3
Cl
O
O
HN
e, f
HN
g, b
CF3
CF3
Cl
O
N
O
O
O
N
H
N
31
33
32
Scheme 4. Synthesis of compounds 28–30 and 33. Reagents and conditions: (a) NBS, CH3CN/MeOH/TFA, 60 °C or NCS, CH3CN/MeOH / TFA, 60 °C; (b) TMSCl, NaI, CH3CN, rt;
(c) Zn(CH3)2, PdCl2(dppf)⁄CH2Cl2, Dioxane, 80 °C; (d) PhB(OH)2, PdCl2(dppf)⁄CH2Cl2, Dioxane/H2O, K2CO3, 160 °C, W, 20 min; (e) t-BuLi, THF, À78 °C, then added to ethyl 3-
methyl-2-oxobutyrate, THF, À78 °C; (f) (i) Cl3CCONCO, DCM, rt, (ii) 1 M K2CO3 (aq), reflux; (g) 2-naphthalenylboronic acid, PdCl2(dppf)⁄CH2Cl2, Dioxane/H2O, K2CO3, 160 °C,
W, 20 min.
l
l
for further improving DMPK properties while maintaining excel-
lent potency. Our hit to lead optimization resulted in the discovery
of highly potent and orally bioavailable EP3 receptor antagonists
such as 29, which is a valuable tool for the biomedical research
community to further identify and validate potential therapeutic
benefits of selective EP3 inhibition.
Table 5
Potency of enantiomers 34 and 35
O
O
O
O
HN
HN
(R)
O
(S)
O
O
Acknowledgements
O
N
H
N
H
We thank William Leister for chiral HPLC and Doug Minick for
VCD support. A.I.M. thanks Dr. Wilma Febo-Ayala for helping on
preparing the manuscript.
35
34
Compounds
Stereochemistry
hEP3 FLIPR fpKi
34
35
R
S
7.7
8.1
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28. fpKi calculation is detailed in supporting information of Ref. 27.
29. The biological assay results in this paper are
a mean of at least 2
determinations with standard deviation of < 0.3 unless otherwise noted.
30. For an alternative synthetic approach see Ref. 27.
31. Li, Y. H.; Zhang, L.; Tseng, P.-S.; Zhang, Y.; Jin, Y.; Shen, J.; Jin, J. Tetrahedron Lett.
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32. All studies were conducted after review by the GSK Institutional Animal Care
and Use Committee and in accordance with the GSK Policy on the Care, Welfare
and Treatment of Laboratory Animals.
33. The enantiomers 34 and 35 were separated using the following chiral HPLC
conditions: Chiralpac AS column (2 Â 25 cm); 100% MeOH, 1 mL/min elution;
dual UV detector (220 nm and 254 nM); Rt = 3.74 min (peak 1); Rt = 6.37 min
(peak 2).