Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia

Article abstract of DOI:10.1021/acsmedchemlett.7b00383

Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA₁) antagonist 4. Wash-out experiments using rat isolated urethra showed that

Full text of DOI:10.1021/acsmedchemlett.7b00383

Letter
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Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX-XXX
Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302)
for the Treatment of Benign Prostatic Hyperplasia
Masahiko Terakado,*,† Hidehiro Suzuki,§ Kazuya Hashimura,† Motoyuki Tanaka,† Hideyuki Ueda,†
Keisuke Hirai,† Masaki Asada,† Masahiro Ikura,† Naoki Matsunaga,† Hiroshi Saga,§ Koji Shinozaki,§
Naoko Karakawa,§ Yuka Takada,§ Masashi Minami,§ Hiromu Egashira,† Yoshihiro Sugiura,#
Masanori Yamada,# Shinji Nakade,§ and Yoshikazu Takaoka†
§
#
†Medicinal Chemistry Research Laboratories, Exploratory Research Laboratories, and Discovery Research Laboratories, ONO
Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
S
* Supporting Information
ABSTRACT: Scaffold hopping from the amide group of lead compound ONO-
7300243 (1) to a secondary alcohol successfully gave a novel chemotype
lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments
using rat isolated urethra showed that compound 4 possesses a tight binding
feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to
pyrrole and an indane moiety afforded an optimized compound ONO-0300302
(19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced
increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg,
p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the
observed long duration action is because of the slow tight binding character of 19.
KEYWORDS: LPA1 antagonist, GPCR, slow tight binding antagonist, benign prostatic hyperplasia, SAR, lead optimization
mproved in vivo efficacy is a major goal of drug discovery
based lead optimization campaigns. To increase the in vivo
BPH, such as tamsulosin or doxazosin, are clinically used as a
single daily dose. Therefore, our main goal is to develop a novel
LPA1 antagonist that shows highly potent IUP reduction
efficacy and good duration of action to meet the single daily
dose requirement.
I
potency and pharmacokinetic (PK) profiles, some general
strategies are known, such as blocking of the metabolic labile
part1 and conformational restriction.2 Recently, residence time,
which implies that a compound binds tightly to the target
protein, has attracted attention because of the long biological
effect of the compound in vivo.3 In this report, we describe in
vitro and in vivo structure−activity relationship (SAR) studies
during the lead optimization campaign of an LPA1 antagonist
for the treatment of benign prostatic hyperplasia (BPH). We
also discuss the relationship between the slow and tight binding
character and the in vivo efficacy of the LPA1 antagonist.
As described in our previous paper,4 we have successfully
obtained the lead compound ONO-7300243 (1), which is a
new chemotype LPA1 antagonist.5−8 Compound 1 is orally
active against the lysophosphatidic acid (LPA) induced rat
intraurethral pressure (IUP) model9,10 in a dose-dependent
manner. Moreover, this compound (30 mg/kg, p.o.) signifi-
cantly reduced the IUP in a conscious rat without the LPA
stimulation, and it did not affect the mean blood pressure
(MBP). Tamsulosin (an α1 adrenoceptor antagonist) is
clinically used for BPH treatment but induces postural
hypotension at clinical doses. We found that tamsulosin also
reduces IUP in the same in vivo model at 1 mg/kg oral
administration and also showed significant MBP reduction at
the same doses. These results suggest that an LPA1 antagonist
is required as an alternative option for BPH treatment, which
does not affect blood pressure. Generally, most of medicines for
For this purpose, the PK profile of the lead compound 1
required improvement to ensure better in vivo efficacy. As we
already reported,4 1 has a rapid clearance (CLtot = 15.9 mL/
min/kg at 3 mg/kg i.v.) and a short half-life (0.3 h). The in vitro
metabolic study in rat and human liver microsomes indicated
that the 3-phenylpropyl moiety of 1 is metabolically labile. We
initially tried to modify the 3-phenylpropyl part of 1 to improve
its metabolic stability. Modification of the 3-phenylpropyl
group to a 3-phenyl-2-propenyl group (2) did increase the
microsomal stability. However, introduction of the sp2 carbon
caused an unfavorable loss of antagonistic activity (Figure 1).
Furthermore, we attempted to introduce various substituents
into the phenyl ring but failed to improve the metabolic
stability. Thus, modification of this moiety proved difficult with
respect to maintaining a balance between the antagonist activity
and the metabolic stability. Consequently, an alternative
approach to improve the in vivo activity was required.
We next tried to modify the amide part to a different
template. Scaffold hopping is generally considered an effective
approach to change the properties of compounds.11 Various
Received: September 19, 2017
Accepted: November 20, 2017
Published: November 20, 2017
© XXXX American Chemical Society
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Figure 2. Wash-out experiments of compounds 1 and 4 using rat
isolated urethras (y axis shows % inhibition of LPA induced rat isolated
urethra contraction, means SD, n = 3). Ten micromolar LPA was
added into a medium to measure the extent of a rat isolated urethra
(100% control). After exchanging the medium, a test compound (1
μM) was added and incubated for 30 min. Ten micromolar LPA was
added to record the extent of contraction (Compound). The urethra
was washed out with media (no compound) three times every 10 min.
Ten micromolar LPA was added to record the extent of contraction
(Wash-out 1). The wash-out procedure was repeated (Wash-out 2).
(A) Inhibition by compound 1 was reduced after the wash-out
procedure. (B) Inhibition by compound 4 was unaffected after two
wash-outs.
Figure 1. Modification of lead compound 1. aIC50 values were
determined by nonlinear regression analysis of the dose−response
curves (4 points) generated using GraphPad Prism ver. 5.04 with 95%
confidence intervals in parentheses. The LPA1 receptor stably
expressed in CHO cells was used. brMS, rat microsomal stability;
hMS, human microsomal stability; 0.5 mg/mL NADPH.
Further modification was conducted using this secondary
alcohol structure as a template. Various N-alkylated hetero-
aromatic analogs of compound 4 were synthesized using the
intermediate S16 (Scheme S3, see Supporting Information)
and tested for in vitro LPA1 antagonist activity. The results are
summarized in Table 1. Imidazole analog 5 resulted in a three-
fold decrease in the potency when compared with that of 4.
Changing to 1,2-pyrazole analogues (6 and 8) increased the
potency of 4 by ∼2-fold. The addition of a dimethyl group to
compound 6 resulted in the loss of potency (7). This is
postulated to be due to steric hindrance. Changing to a pyrrole
derivative (9) caused a further increase in potency. The relative
order of the antagonist activity is pyrrole (9) > 1,2-pyrazole (6,
8) > benzene (4) > imidazole (5).
We next changed the tether length between the aromatic ring
and the carboxylic acid. One carbon elongation of the 1,2-
pyrazole analogues (6, 8) gave the propionic acid derivatives
(11, 12), respectively, which showed similar antagonist activity
as the parent species. In the case of the pyrrole derivative, the
propionic acid analog 13 had significantly reduced antagonist
activity when compared with the acetic analog 9. Shortening
compound 9 by one carbon gave compound 10, which resulted
in a significant loss of potency. At any tether length, the pyrrole
derivatives gave better antagonist activity among the hetero-
aromatic rings synthesized.
To define the functional role of the pyrrole ring, a docking
study using the X-ray crystal structure of LPA1 (PDB ID:
4z34)12 with compound 9 was conducted. The result is shown
in Figure 3. The binding mode of compound 9 is almost the
same as the one of the original ligand bound in the X-ray crystal
structure.12 In addition, the amine group of Lys39 was located
above the pyrrole group of compound 9. The interaction
distance between the pyrrole ring and the amine group of
Lys39 is 3.7 Å. As described above, the antagonist activity
becomes stronger in the order pyrrole >1,2-pyrazole > benzene
> imidazole. This order correlates with the order of cation−pi
interactions, which has been reported in the literature.13 Under
the physiological conditions studied, we speculate that the
amine residue of Lys39 is protonated and the pyrrole of
compound 9 interacts with the cationic amine. We hypothesize
attempts of introducing bioisosteres including five-membered
aromatics failed. However, during this process we found that
transformation of the amide group to a ketone group (3)
retained antagonist activity (Figure 1, see Supporting
Information Scheme S1 for synthesis of compound 3).
Reduction of the ketone 3 gave two diastereomers, each a
50:50 mixture of enantiomers, which also retained antagonist
activity. The four stereoisomers were separated using HPLC
(Scheme S2) and the antagonist activity was tested in vitro. One
isomer (4) was found to have increased antagonist activity in
vitro when compared with that of compound 1. Determination
of the absolute and relative stereochemistry of the active isomer
was accomplished by an alternative synthesis, as depicted in
Schemes S3 and S4.
Compound 4 was tested via oral administration for
evaluating the effects on the LPA induced rat IUP model.
Compound 4 inhibited the LPA-induced IUP increase in a
dose-dependent manner (ID50 = 0.97 mg/kg p.o.) after 1 h of
an oral dose. In addition, we sought to identify the difference in
the mode of action between amide 1 and the secondary alcohol
4. The biological activities of 1 and 4 were examined in rat-
isolated urethras using a Magnus apparatus. Both compounds
inhibited LPA induced rat urethra contraction. However,
inhibition by amide 1 was found to reduce gradually as the
wash-out was repeated (Figure 2). However, inhibition by
alcohol 4 was not affected by the wash-out process. These
results suggest that alcohol 4 has a tight binding feature to the
LPA1 receptor. We speculate that this character improved the in
vivo efficacy of compound 4. This observation may be due to
the different hydrogen bond networks formed by amide 1 and
alcohol 4. The secondary amide group of compound 1 only acts
as a hydrogen bond acceptor. The alcohol group, which is
present in compound 4, acts as a hydrogen bond donor and/or
acceptor. We hypothesize that this difference in binding mode
leads to tight binding of compound 4 to the LPA1 receptor.
Thus, we successfully changed the core structure from the
amide to the secondary alcohol scaffold.
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Table 1. Effects of Various Five- Membered Heteroaromatics and Tether Lengths
a
IC50 values were determined by nonlinear regression analysis of the dose−response curves (4 points) generated using GraphPad Prism ver. 5.04
with 95% confidence intervals in parentheses. The LPA1 receptor stably expressed in CHO cells was used.
compounds (18 and 19) showed moderate stability against rat
microsomes, which suggests a poor in vivo efficacy. However, as
mentioned above for compound 4, the alcohol template has a
tight binding feature that should give good in vivo efficacy.
Thus, all compounds in Table 2 were evaluated in the rat IUP
model (Figure 4A).
When LPA was injected intravenously into rat, the IUP
increased by ∼6 mmHg (Figure 4A, vehicles). Compound 14
decreased significantly the LPA-induced IUP increase to 1.31
mmHg (75% inhibition p < 0.001 vs vehicle, see Supporting
Information Table S1) after 1 h at 3 mg/kg oral dosing. The
effect of compound 14 was weaker than the effect of compound
9 at 3 h and was not observed at 6 h (23% inhibition, no
significance vs vehicle). Other thiophene analogues (15−17)
were evaluated at 3 and 6 h to determine if these compounds
Figure 3. Docking results for compound 9 using the LPA1 structure
(PDB ID: 4z34).12 Hydrogen atoms are omitted for clarity.
have a longer duration of action when compared with
compound 14 (Figure 4A). All compounds were significantly
effective at 3 h with a reduction in the IUP increase to ∼2
mmHg (∼70% inhibition). However, the inhibition was not
retained to 6 h, probably because of poor metabolic stability
(Table 2).
that this interaction makes the pyrrole analog 9 the most
potent.
The in vivo potency of compound 9 was evaluated against the
LPA induced rat IUP model, and an ID50 of 0.6 mg/kg was
determined after 1 h oral dosing. This ID50 is very similar to the
value determined for compound 4. The duration of action of 9
was not sufficient (33% inhibition for 6 h using rats) due to its
poor PK profile (CLtot = 50 mL/min/kg). Thus, we attempted
to modify the 3-phenylpropyl moiety of compound 9, which is
suspected to be labile to hepatic metabolism, as discussed
previously.4
The in vitro activities of these modified compounds are
summarized in Table 2. Most substitutions on the phenyl ring
and side chain were found to be detrimental to the antagonist
activity. In the alcohol series, however, it was discovered that 2-
or 3-substituted thiophenes (14−17) retained antagonist
activity. Moreover, surprisingly, the incorporation of the indane
structure into this moiety was tolerated for activity. Acetic acid
type compounds (14, 16, and 18) tended to have stronger
activity than the corresponding propionic acids (15, 17, and
19).
The best result was obtained by incorporation of the indane
structure into the 3-phenylpropyl moiety. Compound 18
significantly reduced the IUP increase by up to 3.33 mmHg
(52% inhibition, p < 0.05 vs vehicle) until 12 h. Compound 19
(a propionic acid analog of 18) showed even better reduction
of the IUP increase (47% inhibition at 18 h, p < 0.01 vs
vehicle). Moreover, compounds 18 and 19 were evaluated in a
dog IUP model (Figure 4B) because the BPH in human and
dog has common features.14 In dog, compounds 18 and 19
gave good efficacy and duration of action (Figure 4B). In
particular, compound 19 showed 30% inhibition after 24 h at 1
mg/kg oral dosing. Thus, our approach has successfully
obtained the optimized compound 19 (ONO-0300302).
We were interested in the possible excellent in vivo activity of
19, despite its moderate in vitro antagonist activity and
nonsustainable PK profile in rat. We conducted further
experiments to investigate the differences among the derivatives
to explain the PK/PD correlation.
The metabolic stability of the compounds using rat and
human microsomes were also examined (Table 2). The
metabolic stabilities of the compounds against human micro-
somes were found to be generally good. However, some
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Table 2. Exploration of the 3-Phenylpropyl Moiety
a
IC50 values were determined by nonlinear regression analysis of the dose−response curves (4 points) generated using GraphPad Prism ver. 5.04
b
with 95% confidence intervals in parentheses. The LPA1 receptor stably expressed in CHO cells was used. 0.5 mg/mL, NADPH. MS: microsomes.
c
d
i.v. dose of 1 mg/kg. N.T. = not tested.
Figure 4. In vivo efficacy and duration of action against LPA induced rat and dog IUP. (A) Compound or vehicle (20% STPG) was orally
administered at 3 mg/kg in conscious rats. After the prescribed time (1, 3, 6, 9, 12, 18, and 24 h), LPA (300 μg/kg) was injected intravenously and
the IUP measured in short-term anesthetized rats. (B) Compound was orally administered at 1 or 3 mg/kg in conscious dogs. LPA (300 μg/kg) was
injected intravenously at each point (0.5, 1, 2, 4, 6, 9, 12, and 24 h), and the IUP was measured in conscious dogs. Each datum was shown as a %
response, which is compared with the IUP of predosing (0 h) in each dog (%pre).
D
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Figure 5. Binding experiments. Saturation binding for tritium labeled compounds to membranes of the LPA1 receptor expressed in CHO cells. Kd
values were determined by fitting curves with one-site binding (hyperbola) using GraphPad Prism ver. 5.04. (A) Specific binding curves for [3H]-
compound 19 at different incubation times. (B) Specific binding curves for [3H]-compound 1 at different incubation times. (C) Effect of
temperature. (D) Correlation between binding (Ki) and in vivo i.v. efficacy (ID50). Ki values were measured at 37 °C for 2 h using 1 nM [3H]-ONO-
0300302 and calculated with the Cheng−Prusoff equation (Ki = IC50/(1 + [radioligand]/Kd)). ID50 was estimated in the LPA induced rat IUP
model via i.v. dosing (3 doses, n = 1).
Currently, GPCR downstream Ca2+ mobilization at 10 min
incubation time is used as the indicator of compound affinity
with the LPA1 receptor. However, no correlation was found
between Ca2+ mobilization and in vivo activities, as described
above. Thus, a binding experiment was conducted to measure
the affinity directly between a compound and the LPA1
receptor. Tritium labeled lead compound 1 ([3H]-ONO-
7300243) and the optimized compound 19 ([3H]-ONO-
0300302) were synthesized via tritiation of the corresponding
olefin analogs of compounds 1 and 19.15 The binding
experiments were conducted with different incubation times
at room temperature. Saturation binding curves to the
membrane fraction of LPA1 expressed CHO cells are presented
in Figure 5A,B. Dissociation constants (Kd) are summarized in
the tables in Figure 5A−C. The Kd values for [3H]-compound
19 were found to be lower as the incubation time increased (Kd
= 0.49 nM at 4 h). This indicates that the binding affinity of
compound 19 increases with time, which means compound 19
is a slow binding inhibitor. Conversely, the Kd values of the
amide compound 1 did not change with the incubation time.
The minimum Kd value of compound 19 (Kd = 0.34 nM)
was observed at 37 °C and after 2 h (Figure 5C). Using these
binding assay conditions (37 °C, 2 h, 1 nM [3H]-ONO-
0300302), the Ki values of our in-house LPA1 antagonists were
measured. At the same time, their in vivo potency (ID50) was
evaluated in the rat LPA induced IUP model via i.v. dosing.
Figure 5D shows a good correlation between the in vivo ID50
and the in vitro Ki values (R2 = 0.68). The human LPA1
receptor shares high sequence homology (97.3% identity) with
the rat LPA1 receptor (Figure S1, see Supporting Information).
In addition, 61/62 residues within 8 Å of ligand binding site are
conserved in human and rat LPA1 receptors (Figure S2). These
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analyses ensure the usefulness of the rat and dog IUP models.
We believe this slow tight binding feature to the LPA1 receptor
leads to the strong in vivo efficacy and the long duration of
action of the optimized compound 19.
Finally, the IC50 value of 19 was re-evaluated in the LPA1
receptor expressed CHO cells by taking into account the slow
binding. The compound was tested using a long time
incubation method and wash-out experiment in CHO cells
(Figure S3, see Supporting Information). Compound 19 was
added into the assay wells at the beginning of cell seeding and
incubated with the CHO cells for 24 h. The concentration of
the compound was held at the same concentration during a
loading Ca2+ indicator and after stimulation by LPA. This long
time incubation without the wash-out step gave an IC50 value
for 19 of 0.16 nM (0.094−0.27 nM, 95% confidence intervals).
When the compound was washed out before LPA stimulation,
the IC50 value of 19 was 0.19 nM (0.10−0.36 nM, 95%
confidence intervals). Thus, no significant difference in IC50
values was observed between the two conditions. These results
indicate that 19 is a tight binding inhibitor.
In conclusion, scaffold hopping from the amide group of lead
compound ONO-7300243 (1) gave a secondary alcohol
moiety, which was essential for displaying the tight binding
feature to the LPA1 receptor. Incorporation of an indane
moiety and pyrrole ring afforded the most potent LPA1
antagonist ONO-0300302 (19) among the analogues exam-
ined. Compound 19 shows excellent in vivo efficacy because of
the slow tight binding feature, despite its moderate PK profile,
and it represents the best research tool available to shed light
on BPH patients and LPA-related diseases.
ASSOCIATED CONTENT
■
S
* Supporting Information
(10) Saga, H.; Ohhata, A.; Hayashi, A.; Katoh, M.; Maeda, T.;
Mizuno, H.; Takada, Y.; Komichi, Y.; Ota, H.; Matsumura, N.;
Shibaya, M.; Sugiyama, T.; Nakade, S.; Kishikawa, K. A novel highly
potent Autotaxin/ENPP2 inhibitor produces prolonged decreases in
plasma lysophosphatidic acid formation in vivo and regulates urethral
tension. PLoS One 2014, 9, e93230.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.7b00383.
Experimental procedures and characterization for the
synthesis of 3−19, biological assay protocols, Table S1,
and Figures S1−S3 (PDF)
(11) Bohm, H. − J.; Flohr, A.; Stahl, M. Scaffold hopping. Drug
Discovery Today: Technol. 2004, 1, 217.
(12) Chrencik, J. E.; Roth, C. B.; Terakado, M.; Kurata, H.; Omi, R.;
Kihara, Y.; Warshaviak, D.; Nakade, S.; Asmar-Rovira, G.; Mileni, M.;
Mizuno, H.; Griffith, M. T.; Rodgers, C.; Han, G. W.; Velasquez, J.;
Chun, J.; Stevens, R. C.; Hanson, M. A. Crystal structure of antagonist
bound human lysophosphatidic acid receptor 1. Cell 2015, 161, 1633−
1643.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +81-75-961-1151. Fax: +81-75-962-9314. E-mail:
terakado@ono.co.jp.
ORCID
(13) Mecozzi, S.; West, A. P., Jr.; Dougherty, D. A. Cation-pi
interactions in aromatics of biological and medicinal interest:
Electrostatic potential surfaces as a useful qualitative guide. Proc.
Natl. Acad. Sci. U. S. A. 1996, 93, 10566−10571.
(14) Mahapokai, W.; Van Sluijs, F. J.; Schalken, J. A. Models for
studying benign prostatic hyperplasia. Prostate Cancer Prostatic Dis.
2000, 3, 28−33.
(15) The preparation of labeled compounds was conducted at a
contract research laboratory, Sekisui Medical Co., Ltd. (former Daiichi
Pure Chemicals Co., Ltd.).
Masahiko Terakado: 0000-0002-4740-1667
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. T. Maruyama for his helpful suggestions during
the preparation of this manuscript.
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