Discovery of novel seven-membered prostacyclin analogues as potent and selective prostaglandin FP and EP3 Dual Agonists

Article abstract of DOI:10.1021/acsmedchemlett.6b00415

A novel series of prostaglandin analogues with a seven-membered ring scaffold was designed, synthesized, and evaluated for the functional activation of prostaglandin receptors to identify potent and subtype-selective FP and EP3 dual agonists. Starting fro

Full text of DOI:10.1021/acsmedchemlett.6b00415

Letter
pubs.acs.org/acsmedchemlett
Discovery of Novel Seven-Membered Prostacyclin Analogues as
Potent and Selective Prostaglandin FP and EP3 Dual Agonists
Isamu Sugimoto,*,†,¶ Tohru Kambe,† Tomotaka Okino,§ Tetsuo Obitsu,† Nobukazu Ohta,†
Taihei Nishiyama,† Akihiro Kinoshita,† Taku Fujimoto,† Hiromu Egashira,† Shinsaku Yamane,‡
Satoshi Shuto,¶,# Kousuke Tani,§ and Toru Maruyama†
‡
§
†Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono
Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan
#
¶Faculty of Pharmaceutical Sciences and Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12,
Nishi-6, Kita-Ku, Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: A novel series of prostaglandin analogues with a
seven-membered ring scaffold was designed, synthesized, and
evaluated for the functional activation of prostaglandin receptors
to identify potent and subtype-selective FP and EP3 dual
agonists. Starting from the prostacyclin derivative 5b, a
nonselective agonist for prostaglandin receptors, replacement of
the core structure with an octahydro-2H-cyclopenta[b]oxepine
scaffold led to the discovery of the potent and selective FP and
EP3 dual agonist 11b as a lead compound for the development of
an antiglaucoma agent.
KEYWORDS: Prostaglandin, dual agonist, FP receptor, EP3 receptor, GPCR, glaucoma
rostaglandins are the products of cyclooxygenase-catalyzed
metabolism of arachidonic acid that exert a wide variety of
P
biological actions through G-protein coupled prostaglandin
receptors. Prostaglandin E2 (PGE2), PGF2α, PGD2, PGI2, and
thromboxane A2 (TXA2) preferentially activate the EP, FP, DP,
IP, and TP receptor, respectively. There are four distinct
subtypes of EP receptor, EP1, EP2, EP3 and EP4, as well as two
subtypes of DP receptor, DP1 and DP2.
Glaucoma is a chronic ocular disease characterized by
progressive optic neuropathy and visual field loss. There are
many types of treatment for glaucoma based on various
mechanisms. The primary treatment is to control intraocular
pressure (IOP) by topical administration of an IOP lowering
agent. Prostaglandin analogues (PGAs) such as latanoprost,1
travoprost,2 and tafluprost3,4 (Figure 1) reduce IOP by
targeting the prostaglandin FP receptor. Currently, such FP
agonists are the most effective IOP-lowering agents. However,
recently, a novel mechanism of action for PGAs via the
prostaglandin EP3 receptor has been reported.5,6 Topically
applied EP3 receptor agonists have demonstrated the potential
to reduce IOP in animals.7 These findings inspired us to
identify a small molecule that selectively activates both the FP
and EP3 receptors, which could potentially have a superior
IOP-lowering effect compared with PGAs.8 Herein, we report
discovery of the first highly selective FP and EP3 dual agonists
with a novel seven-membered prostacyclin scaffold, (5aR,8aS)-
octahydro-2H-cyclopenta[b]oxepine.
Figure 1. Launched antiglaucoma prostaglandin analogues.
To the best of our knowledge, no potent and selective FP
and EP3 dual agonists have been reported. We conducted
compound screening of our in-house compound libraries to
identify compounds possessing FP and EP3 dual agonist
activity. Through this screening, compounds 4, 5a, and 5b were
found to show the desired activities. The activity profiles are
summarized in Table 1, including data for latanoprost acid (1),
travoprost acid (2), and sulprostone (3, Figure 2)9 for
comparison. Latanoprost and travoprost selectively stimulate
Received: October 19, 2016
Accepted: December 13, 2016
Published: December 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.6b00415
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of the molecule in the receptor binding site. Second, the seven-
membered ring scaffold may more effectively mimic the
conformationally flexible structure of natural prostaglandins,
such as E2 and F2α, compared with the six-membered ring. If
the FP and EP3 receptors prefer a ligand with conformationally
flexible features for the active binding mode, a prostacyclin
analogue with a seven-membered ring might more effectively
stimulate these receptors. If the IP receptor prefers a more rigid
ligand structure in its binding, a ligand with a seven-membered
ring would be less potent toward the IP receptor. Finally,
variations in the length, position, and configuration of the
carboxylic acid chain on the seven-membered ring scaffold will
effectively change the three-dimensional relationship between
the carboxyl group and the terminal phenyl ring. The relative
position of these groups is likely to be important for the active
binding mode stimulating both FP and EP3 receptors.
Therefore, varying the positions of these groups could change
the potency and selectivity of the compounds toward the
receptors, and the appropriate positions of the groups for an FP
and EP3 dual agonist can be explored. Thus, ring expansion
from a six to a seven-membered prostacyclin analogue would be
a rational and promising entry toward the discovery of an FP
and EP3 dual agonist with high potency and subtype selectivity.
To our knowledge, no prostacyclin analogues of this type
containing a seven-membered ring have been reported to date.
Based on the above-mentioned findings and considerations,
we designed and synthesized a collection of novel prostacyclin
analogues containing a seven-membered ring structure with
variations in the length, position, and configuration of the
carboxylic acid chain (Figure 4). All the compounds have a
common terminal phenoxy group in their ω-chains, suggesting
potent agonist activity against both FP and EP3 receptors. Type
A compounds (6−9) have an unsaturated core structure,
5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepine, with a car-
boxylic acid chain at the 3-positon. Type B (10a−12b) and
Table 1. Activity Profiles of Identified Compounds
a
functional assay (EC50, nM)
compound
hFP
hEP3
hIP
b
4
16
0.89
4.1
NT
5a
5b
1
4.1
7.1
12
26
3.6
47
8600
3400
0.34
>10000
>10000
>10000
2
3.6
1800
3
a
Assay protocols are provided in the Supporting Information. EC50
b
values represent the mean of at least two experiments. Not tested.
Figure 2. Structures of sulprostone and prostacyclin (PGI2).
the FP receptor, while sulprostone is a potent EP3 receptor
agonist. All three hit compounds have a terminal phenyl ring in
their ω-chain, which is a structural feature shared with
latanoprost, travoprost, and sulprostone. These results indicate
that the terminal phenoxy group may be a privileged structure
for potent FP and EP3 receptor dual agonists. Although 16-
phenoxy tetranor PGE2 (4) exhibited agonist activity against
both the FP and EP3 receptors, the chemical lability of 4 in
aqueous solution because of the β-hydroxyl ketone structure
was a major drawback for development as an ocular
formulation. Therefore, we turned our attention to 5a and 5b
previously reported by the Upjohn group.10 Both 5a and 5b
showed potent EP3 and FP activity, as well as the expected
chemical stability in aqueous solution as required for an ocular
formulation, but also demonstrated agonist activity against the
IP receptor. It has been reported that activation of the IP
receptor may cause conjunctival irritation.11,12 We therefore
attempted to identify compounds possessing potent and
selective agonist activity for both the FP and EP3 receptors
over the IP receptor by the structural modification of 5a and 5b
(Figure 3).
Figure 3. Compounds with dual FP and EP3 agonist activity found
from compound libraries.
Since prostacyclin, PGI2, exhibits highly potent activity for
the IP receptor, the IP agonist activity of 5a and 5b is probably
due to their core structural similarity to prostacyclin.
Compounds 5a and 5b have a homoprostacyclin scaffold,
octahydrocyclopeta[b]pyran. Further homologation, namely,
ring expansion from a six- to a seven-membered ring, should
affect their physicochemical and pharmacological properties in
a predictable fashion. First, the extra methylene group in the
core structure should increase the lipophilicity and the volume
Figure 4. Designed compounds with seven-membered ring scaffolds.
B
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a
Scheme 1. Synthesis of Type A and Type B Compounds
a
Reagents and conditions: (a) TBSCl, imidazole, DMF, rt; (b) DIBAL, toluene, −60 °C; (c) Ph3PCH3Br, t-BuOK, 0 °C, 95% in 3 steps; (d) NaH,
2,3-dibromopropene, DMF, 0 °C, 82%; (e) EtO2C(CH2)n+1ZnBr, Pd(t-Bu3P)2, toluene, THF, 80 °C, 86−97%; (f) (SIMes)Ru(PCy3) (Ind)Cl2,
toluene, 80 °C, 83−92%; (g) aq. NaOH, EtOH, rt; (h) 2-iodopropane, K2CO3, DMF, 40 °C, 90−99%; (i) TBAF, THF, rt, 47−96%; (j) SO3·
pyridine, i-Pr2NEt, AcOEt, 0 °C; (k) dimethyl (2-oxo-3-phenoxypropyl)phosphonate, K3PO3, THF, rt, 43−69% in 2 steps; (l) (R)-2-methyl-CBS-
oxazaborolidine, BH3·SMe2, THF, rt; (m) AcOH, H2O, THF, 60 °C, 20−67% in 2 steps; (n) aq. NaOH, MeOH, rt, 94%−quant.; (o) H2, Pd/C, i-
PrOH, rt or H2, PtO2, AcOEt, rt or H2, [Ir(cod) (PCy3) (py)]PF6, CH2Cl2, rt; (p) HPLC or SFC separation.
a
Scheme 2. Synthesis of Type C Compounds
a
Reagents and conditions: (a) RuClH(CO) (PPh3)3, toluene, 60 °C, 94%; (b) t-butyl bromoacetate, NaH, DMF, rt, 72%; (c) aq. NaOH, MeOH,
THF, rt; (d) allyl bromide, K2CO3, DMF, rt, 90% in 2 steps; (e) LDA, TMSCl, THF, −78 °C to rt; (f) TMSCHN2, MeOH, AcOEt, rt, 32% and 35%
in 2 steps; (g) (SIMes)Ru(PCy3) (Ind)Cl2, toluene, 80 °C, 80−85%; (h) LiAlH4, THF, 0 °C, 89−92%; (i) Ph3PCHCO2iPr, 2-iodoxybenzoic acid,
DMSO, rt, 83−90%; (j) H2, Pd/C, NaHCO3, i-PrOH, rt, 75−86%; (k) TBAF, THF, rt, 78−87%; (l) SO3·pyridine, i-Pr2NEt, AcOEt, 0 °C; (m)
dimethyl(3-phenoxy-2-oxopropyl)phosphonate, K3PO4, THF, rt, 44−46% in 2 steps; (n) (R)-2-methyl-CBS-oxazaborolidine, BH3·SMe2, THF, rt;
(o) AcOH, H2O, THF, 60 °C, 56−63% in 2 steps; (p) aq. NaOH, MeOH, rt, quant.
C
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Table 2. Functional Potency toward Human Prostaglandin Receptors for Compounds 6−13
a
Assay protocols are provided in the Supporting Information. EC50 values represent the mean of at least two experiments.
type C (13a and 13b) compounds have a 3,4,5,5a,6,7,8,8a-
octahydro-2H-cyclopenta[b]oxepine core scaffold substituted
with carboxylic acid chains at the 3- and 2-positions,
respectively.
purification followed by saponification gave diastereomerically
pure acids 10a−12a and 10b−12b.
The syntheses of the type C compounds are outlined in
Scheme 2. Isomerization of the allyl group of compound 15
with RuClH(CO)(PPh3)3 gave the inner alkene 23 as a 1:1
mixture of E and Z isomers. O-Alkylation of alcohol 23
followed by transesterification produced allyl ester 24. Ireland−
Claisen rearrangement of 24 in the presence of LDA and
chlorotrimethylsilane followed by methylation of the resulting
carboxylic acid with trimethylsilyldiazomethane gave methyl
esters 25 and 26, which were readily separable by silica gel
chromatography. Ring-closing metathesis catalyzed by
(SIMes)Ru(PCy3)(Ind)Cl2 gave tetrahydro-oxepines 27 and
28. After reduction with LiAlH4, oxidation of the alcohols to
aldehydes, followed by Wittig condensation with (isopropylox-
ycarbonylmethylene) triphenylphosphorane gave the unsatu-
rated esters. Hydrogenation with palladium on carbon and
deprotection of the TBS group with TBAF gave alcohols 29
and 30. The resulting alcohols were converted to the
corresponding carboxylic acids 13a and 13b as described above.
The activity profiles of the novel prostacyclin derivatives with
a seven-membered ring structure are summarized in Table 2.
The agonist activities of the compounds were evaluated using
intracellular Ca2+ signaling responses in Chinese hamster ovary
(CHO) cells expressing human FP and EP3 receptors and
cAMP signaling responses in CHO cells expressing human IP
receptors.
The syntheses of type A and B compounds are shown in
Scheme 1. A THP-protected Corey lactone 1413 was converted
to allyl cyclopentanol 15 in three steps. Cyclopentanol 15 was
alkylated with 2,3-dibromopropene to afford 16. The Negishi
coupling reaction with corresponding zinc-reagents, followed
by a ring-closing metathesis reaction catalyzed by a ruthenium-
indenylidene precatalyst [(SIMes)Ru(PCy3) (Ind)Cl2]14 af-
forded cyclized compounds 18a−d. Deprotection of the TBS
group with TBAF gave alcohols 20a−d. Oxidation of the
alcohols, followed by Horner−Emmons olefination with
dimethyl (3-phenoxy-2-oxopropyl)phosphonate afforded the
enones. Stereoselective reduction with (R)-2-methyl-CBS-
oxazaborolidine15 and borane-dimethylsulfide complex fol-
lowed by deprotection of the THP group and saponification
gave acids 6−9. For the synthesis of type B compounds,
hydrogenation of tetrahydrooxepine 19a−c with palladium on
carbon, platinum dioxide, or [Ir(cod)(PCy3)(py)]PF6 (Crab-
tree’s catalyst)16 gave a diastereomeric mixture of oxepane
derivatives. After deprotection of the TBS group, introduction
of the ω-chain was carried out in a similar manner as above to
afford isopropylesters 22a−c. High-pressure liquid chromatog-
raphy (HPLC) or supercritical fluid chromatography (SFC)
D
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We first investigated type A compounds bearing unsaturated
core ring structures. However, the FP and EP3 agonist activities
of compound 7 with a C-3 linker were markedly decreased in
comparison with 5a and 5b. Shortening the linker in 6 (C2)
had a smaller effect on agonist activity. Extension of the linker
in 8 (C4) improved the potency for FP and EP3 receptors,
while further extension of the linker in 9 (C5) resulted in less
potency. However, it was noteworthy that IP agonist activity
was completely abolished in all the type A compounds.
We next evaluated type B compounds for agonist activity.
Surprisingly, compound 11a (3α, C3), which has a carboxylic
acid chain with a C-3 linker at the 3-α position, exhibited a
remarkable improvement in EP3 agonist activity and a modest
improvement in FP activity, compared with the corresponding
unsaturated type A analogue 7 (C3). The 3-epimer 11b (3β,
C3) was found to have more potent FP activity than 11a, while
preserving potent EP3 agonist activity. Moreover, the IP
agonist activity of 11a and 11b was completely abolished.
Hence, replacement of the six-membered ring core structure of
5a and 5b with the seven-membered scaffold has a beneficial
impact on subtype selectivity for the FP and EP3 receptors over
the IP receptor. The extra methylene group in the core
structure is unfavorable for an activation of the IP receptor
probably due to steric hindrance. Compounds 12a and 12b
with a C-4 linker maintained FP receptor potency, while the
EP3 agonist activity was greatly reduced. Shortening of the
linker to C-2 in 10a and 10b resulted in a loss of potency for
both FP and EP3 receptors.
Figure 5. Lowest-energy conformations for the more potent
congeners of (a) type C and (b) type B. Superposition of low-energy
conformations for less potent congeners of (c) type C and (d) type B.
which correspond to molecules with the β-configuration of the
type B scaffold and the α-configuration of the type C scaffold,
respectively, exclusively existed as a chair conformation where
the methyl group occupied a pseudoequatorial position (Figure
5a,b). In all the low-energy structures of B-β and C-α observed
within 10 kJ/mol from the global minimum, the conformations
of the seven-membered ring scaffold region were identical to
the most stable conformation. However, the low-energy
conformations of B-α and C-β, which corresponded to the
molecules with the α-configuration of the type B scaffold and
the β-configuration of the type C scaffold, existed as mixtures of
chair/twist-chair and boat conformations (Figure 5c,d).
1
In the H NMR spectra of 11b (3β, C3, type B), the
3
presence of a diaxial JHH coupling of 12 Hz and a higher
We next tested type C compounds, which are regioisomers of
type B. Compound 13b (2β, C2) with a C-2 carboxyl acid side
chain showed the desired potent FP and EP3 agonist activity,
and IP agonist activity was completely abolished. The 2-epimer
13a (2α, C2) exhibited excellent FP and good EP3 agonist
activity, as well as poor IP receptor activity compared with 5a.
Evaluation of the prostacyclin analogues containing a seven-
membered ring revealed that the 2-α congener with a C-2
linker 13a (2α, C2) was the most potent FP agonist among
them. Interestingly, the activity profiles of type B and C
compounds showed an opposite tendency regarding the
configuration of the carboxylic acid chain substituents on the
core scaffolds. In type C compounds, the FP agonist activity of
13a (2α, C2) was 6-fold more potent than that of the
corresponding epimer 13b (2β, C2). For the type B
compounds, however, the congener 11b (3β, C3) was a 10-
fold more potent FP agonist than the corresponding 11a (3α,
C3).
The clear difference in FP agonist activity for these
derivatives, as described above, indicates that the conformation
and configuration of the seven-membered scaffold is critical for
FP receptor recognition. Therefore, we investigated the
conformation of these prostacyclin compounds with seven-
membered ring scaffolds by molecular modeling and 1H NMR.
The results of conformational analysis of type B and C scaffolds
using LIGPREP17 and MACROMODEL18 are shown in Figure
5. To simplify the calculations, we employed model compounds
B-α, B-β, C-α, and C-β, in which the flexible alkyl carboxylic
acid side chain at the 3- or 2-positon and the ω-chain at the 6-
position of the octahydrocyclopenta[b]oxepine were replaced
with methyl and vinyl groups, respectively. Generally, the
conformation of seven-membered ring systems can be
described as a combination of chair/twist-chair and boat/
twist-boat pseudorotational cycles.19 Our calculations showed
that the lowest-energy core ring conformations of B-β and C-α,
magnetic field shift for the H2 signal compared with that for
11a (3α, C3) (2.9 versus 3.4 ppm) indicated that the H3 was in
a pseudoaxial position on the seven-membered ring (Figure S1
1
in the Supporting Information). In the H NMR spectrum of
the type C compounds, the H2 signal of 13a (2α, C2) was
found at higher magnetic field at 3.2 ppm than 13b (2β, C2) at
3.8 ppm. These observations indicated that the carboxylic acid
chains of 11b (3β, C3, type B) and 13a (2α, C2, type C)
occupied pseudoequatorial sites.
The results of modeling and 1H NMR indicate that the most
potent FP agonist 13a (2α, C2, type C) exclusively adopts a
chair conformation, in which the carboxylic acid chain occupies
a pseudoequatorial position. Compound 11b (3β, C3, type B),
which is the most potent of the type B compounds, also adopts
a chair conformation with the carboxylic acid chain in the
pseudoequatorial site. These results suggest that the rigid chair
conformation of the seven-membered core scaffold and the
position of the carboxylic acid group are critical for effective
activation of the FP receptor.
In contrast, EP3 agonist activity was not affected by the
structure of the core ring moiety. Compound 11a (3α, C3) was
the most potent EP3 agonist, while the 3-epimer 11b (3β, C3)
was almost equipotent, regardless of the configuration at the 3-
position. The EP3 agonist activities of 11a and 11b, with a C-3
linker, were 300-fold and 1000-fold more potent than
compounds 10a and 10b with a C-2 linker, respectively, as
well as 50-fold and 100-fold more potent than 12a and 12b (C-
4 linker). These results indicate that the configuration of
substituents is not strictly recognized by the EP3 receptor, and
the length of carboxylic acid chain has a more dominant effect
on EP3 agonist activity.
Therefore, we concluded that 11b, which has a C-3 linked
carboxylic acid side chain with a 3β configuration on a type B
scaffold, was the most appropriate lead compound for further
optimization since it was a potent FP and EP3 dual agonist
E
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with Prostanoid FP-Receptor Agonistic Activity as Potent Ocular-
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(EC50, 28 and 4.0 nM, respectively) but inactive toward the IP
receptor (EC50, > 10 μM). Further evaluation of 11b also
showed that it had less EP1 agonist activity (EC50, 140 nM)
compared with its FP and EP3 activities, and it was inactive
toward EP2 and EP4 receptors with EC50 values of more than
10 μM.
In summary, we have designed and synthesized a novel series
of prostacyclin derivatives with a seven-membered ring scaffold.
Starting from prostacyclin derivative 5b, which is a nonselective
agonist for prostaglandin receptors, replacement of the core
structure of 5b with the novel octahydro-2H-cyclopenta[b]-
oxepine scaffold led us to discover the potent FP and EP3 dual
agonist 11b, which exhibits excellent selectivity over other
prostaglandin receptors. Thus, we have identified 11b as a
promising lead compound for a novel antiglaucoma agent. This
is the first report of seven-membered prostacyclin analogues,
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developing new prostaglandin-related compounds with phar-
macological relevance. Further optimization of the lead
compound will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.6b00415.
■
S
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Experimental procedures, characterization data, and
conditions for the biological assays (PDF)
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AUTHOR INFORMATION
Corresponding Author
*Tel: +81-75-961-1151. Fax: +81-75-962-9314. E-mail: i.
sugimoto@ono.co.jp.
■
(13) Corey, E.; Shirahama, H.; Yamamoto, H.; Terashima, S.;
Venkateswarlu, A.; Schaaf, T. Stereospecific Total Synthesis of
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Indenylidene Complexes: Scope in Cross-Metathesis Transformations.
Adv. Synth. Catal. 2008, 350, 2959−2966.
ORCID
Isamu Sugimoto: 0000-0003-3786-8228
Satoshi Shuto: 0000-0001-7850-8064
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Borane Reduction of Ketones Catalyzed by Chiral Oxazaborolidines.
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Notes
The authors declare no competing financial interest.
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Homogeneous Hydrogenation with [Ir(cod) (PCy3) (py)]PF6. J.
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ACKNOWLEDGMENTS
■
We thank Mr Satoshi Nakayama and Mr. Tomohiro Karakawa
for their efforts on the biological tests, and Ms. Aki Fukunaga
for her help in the SFC separation of compounds.
(17) Schrodinger Release 2016−2: LigPrep, version 3.8; Schrodinger,
̈
̈
LLC: New York, 2016.
(18) Schrodinger Release 2016−2: MacroModel, version 11.2;
̈
Schrodinger, LLC: New York, 2016.
̈
ABBREVIATIONS
■
(19) Jahn, M. K.; Dewald, D. A.; Vallejo-Lopez, M.; Cocinero, E. J.;
̃
THP, tetrahydropyranyl; TBS, tert-butyldimethylsilyl; TBAF,
tetra-n-butylammonium fluoride; LDA, lithium diisopropyla-
mide
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