Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead

Article abstract of DOI:10.1021/acsmedchemlett.6b00225

Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA_1-6. A high throughput screen against LPA₁ gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA₁ antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α₁ adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA₁ antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA₁ antagonists and their in vivo efficacy.

Full text of DOI:10.1021/acsmedchemlett.6b00225

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Letter
Discovery of ONO-7300243 from a novel class of
Lysophosphatidic Acid Receptor 1 antagonists: From hit to lead.
Masahiko Terakado, Hidehiro Suzuki, Kazuya Hashimura, Motoyuki Tanaka, Hideyuki Ueda, Hiroshi Kohno,
Taku Fujimoto, Hiroshi Saga, Shinji Nakade, Hiromu Habashita, Yoshikazu Takaoka, and Takuya Seko
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00225 • Publication Date (Web): 19 Aug 2016
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Discovery of ONO-7300243 from a novel class of Lysophosphatidic
Acid Receptor 1 antagonists: From hit to lead.
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Masahiko Terakado,*† Hidehiro Suzuki, § Kazuya Hashimura,† Motoyuki Tanaka,† Hideyuki Ueda,†
Hiroshi Kohno,† Taku Fujimoto,† Hiroshi Saga,§ Shinji Nakade,§ Hiromu Habashita,† Yoshikazu
Takaoka, † Takuya Seko. †
†Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3ꢀ1ꢀ1 Sakurai, Shimamoto, Mishima, Osaka
618ꢀ8585, Japan
§Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., 17ꢀ2 Wadai, Tsukuba, Ibaraki 300ꢀ4247, Japan
KEYWORDS LPA1 antagonist, GPCR, benign prostatic hyperplasia, SAR, hit-to-lead optimization
ABSTRACT: Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G proteinꢀcoupled
receptors known as LPA1–6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a
led to ONOꢀ7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30
mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist
tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin,
compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA1 antagonists could be used to
treat BPH without affecting the blood pressure. Herein, we report the hitꢀtoꢀlead optimization of a unique series of LPA1
antagonists and their in vivo efficacy.
Lysophosphatidic acids (LPAs) are a bioactive class of
phospholipids, which are produced by autotaxin from
lysophosphatidylcholine in blood.1,2,3 LPAs exerts a wide
range of cellular responses, including intracellular Ca2+
mobilization, cell proliferation, cell survival and cell motility.
Based on their interesting properties, LPAs have been
implicated in a wide range of complex physiological
responses, including the contraction of smooth muscle,
contractile potency to the α1 adrenoceptor agonist
phenylephrine.12,13 It is therefore envisaged that LPA1
antagonist will show good potential for the treatment of BPH.
Several LPA1 antagonists have been reported to date, and
these compounds can be divided into two different categories:
(i) lipid like molecules containing a phosphoric acid moiety
and a long alkenyl chain; and (ii) nonꢀlipid like small
molecules (Figure 1). Compounds belonging to the first group
generally exhibit poor bioavailability because of their high
hydrophobicity. Furthermore, the behavior of these
compounds can readily switch from agonist to antagonist
depending upon the nature of the polar head group, making the
design of antagonists particularly challenging. Most of the
nonꢀlipid small molecules developed to date as LPA1
antagonists are phenylethoxy carbamoyl derivatives, such as
Ki16425, which was the first reported compound to exhibit
demyelization,
wound
healing,
coagulation
and
immunological competence.4 Furthermore, these physiological
functions can be related to a number of pathophysiological
responses, such as cancer,5 neuropathic pain6 and fibrosis.7
The biological effects of LPAs are mediated through G
proteinꢀcoupled receptors (GPCRs). Six LPA receptors (LPA1–
6) have been identified and characterized to date. LPA1,2,3
(previously known EDGꢀ2, 4, 7) belong to the EDG family of
proteins because of their high sequence homology.8,9
LPA1, dual antagonist activities.14 Several analogues of
3
Benign prostatic hyperplasia (BPH) is a chronic disease that
affects around 30% of males over the age of 60 and is
accompanied by the enlargement of prostate and difficulty
urinating. Although the exact causes of BPH are not fully
understood, the prostatic tissue mass and the smooth muscle
tone are thought to be two of the major components of BPH.
One option for the treatment of BPH is to reduce the prostatic
smooth muscle tone using α1 adrenoceptor antagonists such as
tamsulosin or doxazosin, which are currently used in clinical
practice to contract the urethra.10,11 We previously reported
that LPAs can induce the contraction of the urethra via LPA1.
Notably, LPAs have been reported to exhibit similar levels of
Ki16425 have been developed bearing a similar phenylethoxy
carbamoyl moiety to the parent compound but with a wide
variety of different fiveꢀmembered rings to improve their
subtype selectivity and/or in vivo efficacy.14–18 It is noteworthy
that some of these compounds are currently being evaluated in
clinical trials for the treatment of idiopathic pulmonary
fibrosis (IPF). Sanofi Aventis reported a structurally unique
indanꢀ2ꢀcarboxylic acidꢀcontaining antagonist 1. This
compound 1 is most likely an analog of SAR100842, which is
currently in Phase IIa trials for systemic sclerosis.18
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HO2C
structure of LPA1 bound to an antagonist was recently
HO2C
published in the literature.19
1
S
2
3
4
5
6
7
O
O
Cl
H
O
O
Cl
H
CH3
N
CH3
N
Table 1. Structure Activity Relationship for Different
Substituents on Section A
O
CH3
O
N
CH3
N
KIRIN
Ki16425
Amira
AM966
A
C
O
2
3
4
N
8
9
HO2C
OMe
O
R1
O
10
11
12
13
14
15
16
17
18
19
20
21
22
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NH
HO2C
B
O
O
H
N
CO2H
CH3
Cmpd R1
LPA1: IC50 (µM)a
N
N
CH3
CH3
N
7a
7b
7c
7d
7e
7f
4ꢀMeO
4.4
12.1
3.3
(6.9 – 3.1)
Hoffma-La Roche
Sanofi Aventis,1
H
(15.0 – 9.7)
(4.0 – 2.8)
(1.9 – 0.9)
(6.5 – 4.6)
(2.3 – 1.3)
(0.32 – 0.21)
(4.8 – 2.8)
(0.65 – 0.24)
(0.31 – 0.21)
Figure 1. Structures of known LPA1 antagonists
2ꢀMeO
3ꢀMeO
3ꢀF
1.3
At the beginning of our LPA1 antagonist program, the only
small molecule to have been reported in the literature as an
LPA receptor antagonist was Ki16425 with no SAR data.14 To
obtain a good starting point, we carried out a highꢀthroughput
screening (HTS) campaign using a Chinese hamster ovarian
(CHO) cell line stably expressing the human LPA1 receptor. In
this way, we identified compound 7a as a weak LPA1
antagonist (Table 1). Herein, we report the identification of a
novel series of LPA1 antagonists and the results of our
structure and activity relationship (SAR) studies for the
hitꢀtoꢀlead optimization of this series for the treatment of BPH.
5.5
3ꢀMe
1.7
7g
7h
7i
3,5ꢀdiꢀMeO
3,4ꢀdiꢀMeO
0.26
3.7
3,4,5ꢀtriꢀMeO 0.39
3,5ꢀdiꢀMe 0.26
7j
a) IC50 values were determined by nonlinear regression analysis
of the doseꢀresponse curves (5 points) generated using GraphPad
Prism ver.5.04 with 95% confidence intervals in parentheses.
Our initial exploration of the HTS hit compound 7a
involved the modification of section A (blue in Table 1) to
identify the optimum substituent at this position (Table 1). A
variety of different substituted benzene rings were evaluated at
this position, and the results are summarized in Table 1. The
removal of the methoxy group from the benzoyl group
resulted in a 2ꢀfold decrease in the potency. Among the
monoꢀsubstituted compounds (7a, 7cꢀf), the 3ꢀmethoxy analog
7d is the most potent with an IC50 of 1.3 µM. Among the diꢀ
and triꢀsubstituted compounds tested in the current study, the
3,5ꢀdimethoxy analog 7g and 3,5ꢀdimethyl analog 7j were
found to be the most potent. Interestingly, the corresponding
3,4,5ꢀtrimethoxy analog 7i was equipotent with compound 7g,
whereas the monoꢀ and diꢀsubstituted analogs 7c and 7h
showed much lower antagonist activities. These results
therefore highlight the importance of having electronꢀdonating
substituents at the 3ꢀ and 5ꢀpositions of the benzene ring for
good potency.
Docking studies were conducted using the Xꢀray crystal
structure LPA1 (PDB code 4z34)19 to explore the binding
mode of these prototype compounds (10, 13 and 14) and the
importance of the positioning of the carboxylic group (Figure
2Aꢀ2C). The results revealed that the phenyl ring of section A
most likely formed a πꢀstacking interaction with the phenyl
ring of section C. This phenyl ring of section C has a van der
Waals contact with Trp271, Gly274 and Leu275 (see
Supplement, S36, Figure S1A). A similar stacking interaction
to this was also observed in the ligand in the LPA1 Xꢀray
crystal structure19 and represents a common conformational
feature of our LPA1 antagonists. The results of the docking
experiments also revealed that compounds 10 and 13 could
adopt conformations in which their carboxylic acid moieties
interacted with Lys39, His40 and Arg124 in LPA1. These two
compounds would most likely show similar binding modes,
which would explain why they exhibited similar levels of
antagonist activity. In contrast, the docking experiments
revealed that the carboxylic acid moiety of compound 14
could only interact with His40 in LPA1 (Figure 2C),
explaining why this compound was less potent than
compounds 10 and 13.
We subsequently explored section B of hit compound 7a by
varying the substituents attached to the pendent benzoyl
moiety. When the benzoic acid substituent from the original
replaced with phenylacetic acid (8) or
dihydrocinnamic acid (9), the potency remained the same. In
hit was
contrast, the introduction of an ether linker to give a biphenyl
group (10) led to an increase in the antagonist activity (IC50
=
0.089 µM). Furthermore, the orthoꢀ and metaꢀsubstituted
carboxylic acid analogs 10 and 13 were more potent than the
corresponding paraꢀsubstituted derivatives (IC50 = 0.14 µM
for 13, 44% inhibition at 1 µM for 14). These results therefore
suggested that the carboxylic acid group needed to be placed
in a specific position to interact as effectively as possible with
specific basic residues on the target protein. An Xꢀray
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Table 2. Structure Activity Relationship for Section B
1
2
3
4
5
6
O
a
LPA1: IC50 (ꢀM)a
MeO
LPA1: IC50 (ꢀM)
Cmpd
9
X
R2
Cmpd
8
X
R2
N
R2
*
X
*
OMe
H
0.21 (0.28 - 0.16)
H
0.23 (0.30 - 0.18)
HO2C
HO2C
7
8
9
*
*
H
0.089 (0.12 - 0.066)
10
11
0.13
H
(0.17 - 0.11)
13
OMe
Me
(0.21 - 0.098)
O
0.14
O
(0.090 - 0.055)
0.071
12a
HO2C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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40
41
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58
59
60
CO2H
*
*
*
3
Me
4
Me
Me
0.14 (0.19 - 0.10)
12b
12d
H
44% inh at 1 ꢀM
14
O
O
5
6
HO2C
CO2H
Me
*
0.042 (0.050 - 0.036)
12c
(0.022 - 0.010)
Me
0.015
O
O
HO2C
HO2C
Me
*
*
*
*
O
Me
0.10 (0.13 - 0.080)
Me
(0.0073 - 0.0048)
0.0059
12e
12g
12f
O
Cl
HO2C
HO2C
Me
O
Me
Me
Me
(0.0050 - 0.0025)
0.0035
Me
Me
0.68 (0.98 - 0.47)
15
O
HO2C
Cl
CO2H
CO2H
*
*
*
> 1
(0.19 - 0.13)
16
0.16
17a
(ONO-7300243)
CO2H
18a
(0.12 - 0.086)
0.10
O
CO2H
a) IC50 values were determined by nonlinear regression analysis of the doseꢀresponse curves (5 points) generated using GraphPad Prism
ver.5.04 with 95% confidence intervals in parentheses.
the nature of section B moiety. The 3,5ꢀdimethoxyꢀ4ꢀmethyl
substituent was selected as the optimum section A group based
on the potency of compound derivative 12a being greater than
that of the 3,4,5ꢀtrimethoxybenzamide derivative 11.
Compounds 12c and 12d bearing a methyl substituent at the 4ꢀ
or 5ꢀposition of their benzoic acid moiety in section B,
respectively, showed improved antagonist activity compared
with compound 12a. This result indicated that there was
enough space around the benzoic acid group to accommodate
additional substituents at the 4ꢀ and 5ꢀpositions of the benzene
ring. In contrast, compound 12b and 12e bearing a methyl
group at the 3ꢀ or 6ꢀ position of the benzoic acid moiety, did
not improve the potency.
The introduction of an electronꢀwithdrawing chloride at the
4ꢀ or 5ꢀposition of the benzene ring of the benzoic acid moiety
afforded compounds 12f and 12g, respectively, with
considerable increases in the activity compared with the
methyl analogs. Based on these modifications, compound 12g
Figure 2. Docking results for some of our compounds using LPA1
crystal structure (PDB code 4z34)19
bearing
a 3,5ꢀdimethoxyꢀ4ꢀmethylphenyl substituent on
section A and a 5ꢀchloro substituent on section B was
determined to be the most potent antagonist of all of the
compounds synthesized so far. However, the effect of the
chloride atom on the benzoic acid moiety in section B
currently remains unclear, because compounds 12f and 12g
exhibited almost identical activity, despite their different
substitution pattern. It is noteworthy that both of these
Docking poses of compounds (2A) 10 (red), (2B) 13 (blue) (2C)
14 (orange) and (2D) 17a (ONOꢀ7300243). The hydrogen atoms
have been omitted for clarity. The distances are highlighted by
dashed lines (distances in Å).
Further investigation of section B was conducted by fixing
section A as a 3,5ꢀdimethoxy 4ꢀmethyl substituent and varying
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compounds are highly lipophilic (clogP = 8.24) and that phenyl rings of section A and C so that their activities were
increasing lipophilicity can lead to an increase in the activity.20
The addition of a chloride substituent to give compound 12g
led to an increase in the lipophilicity compared with
compound 12d, as well as an increase in activity. In general,
highly lipophilic compounds tend to behave in a promiscuous
manner, hitting multiple targets, which can lead to unwanted
side effects and poor pharmacokinetics.21 With this in mind,
we decided to investigate an alternative strategy for increasing
the antagonist activity without increasing the lipophilicity to
discover a lead compound.
lost. The introduction of an sp2 carbon to this part of the
molecule also led to a decrease in the potency, as
demonstrated by 17b. Notably, the introduction of a fluoro
group at the ortho (17c) or meta (17d) position of the phenyl
ring was tolerated, whereas the para-fluoro analog 17e ablated
activity because of steric repulsion with Trp271 (see
Supplement, S36, Figure S1B). This phenyl propyl moiety is
critical to the antagonist activity.
1
2
3
4
5
6
7
8
Three representative compounds (12g, 17a and 18a) were
studied in an LPAꢀinduced rat intraurethral pressure (IUP)
model (Table 4). This IUP model was conducted as previously
described by the intraduodenal (i.d.) administration of the
compounds.22, 23 Compound 12g, which showed the strongest
in vitro LPAl antagonist activity (IC50 = 0.0035 µM), showed
53% inhibition of LPAꢀinduced IUP increase at 10 mg/kg i.d.
administration. Although ONOꢀ7300243 (17a) showed only
modest in vitro activity (IC50 = 0.16 µM), it showed much
stronger effects in vivo (88% inhibition at 10 mg/kg i.d., 62%
inhibition at 3 mg/kg i.d.) compared with compound 12g. To
develop a deeper understanding of this difference, we
compared the in vitro physicochemical properties of these two
compounds. The results revealed that ONOꢀ7300243 (17a)
showed good membrane permeability and good metabolic
stability against rat liver microsomes (MS). Furthermore, the
molecular weight of ONOꢀ7300243 (17a) was much lower
than that of compound 12g (MW = 461 for 17a, 574 for 12g),
leading to a lower lipophilicity (clog P = 5.29 for 17a, 8.24 for
12g). These data therefore indicate that the good
physicochemical properties of compound 17a led to its good
in vivo efficacy. It is noteworthy that ONOꢀ7300243 (17a) and
compound 18a exhibited good selectivity towards LPAl over
LPA2, most likely because low molecular weight and low
lipophilicity lead to reduced compound promiscuity and
increased selectivity.20 Compounds 17a and 18a exhibited
almost identical levels of antagonist activity in vitro. However,
the in vivo potency of compound 18a was lower than that of
compound 17a. These two compounds have showed similar
physicochemical properties except for their Caco2
permeability. The main difference between compounds 17a
and 18a is the acidity of their carboxylic acid group (i.e., the
pKa value of phenyl acetic acid is 4.3, whereas that of
phenoxyacetic acid is 3.1). This increased acidity could
contribute to decreased membrane permeability and could
explain the reduced in vivo activity (44% inhibition at 10
mg/kg i.d.).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To address this problem, we investigated the possibility of
removing one of the phenyl rings from the bis aryl portion of
the molecule (section B) to decrease the molecular weight
(Table 2, 15ꢀ18a). Although a benzylic phenyl ring was not
essential for inducing antagonist activity in 15, a linker was
required to maintain some distance between the carboxylic
acid and amide functional groups in 16. The activity lost in 16
was recovered by the addition of a spacer, as shown in
compounds 17a and 18a. The results of a docking experiment
with compound 17a using the Xꢀray crystal structure of LPA1
suggested that basic residues in the active site of the protein
could form interactions with acidic functional groups, as
shown in compounds 10 and 13 (Lys39, His40 and Arg124,
Figure 2D). This would explain why compounds 17a and 18a
exhibited similar levels of antagonist activity against LPA1.
Notably, compounds 17a and 18a allowed for a considerable
reduction in the molecular weight, as well as the lipophilicity
(clogP = 5.29 for 17a, 5.23 for 18a).
Table 3. Structure Activity Relationship for Section C
O
MeO
Me
R3
N
OMe
Y
CO2H
LPA1: IC50 (ꢀM)
Cmpd
18b
Y
R3
-OCH2-
-OCH2-
> 10
*
*
*
18c
17b
6.6
> 1
(9.1 - 4.8)
-CH2-
F
-CH2-
-CH2-
*
*
17c
17d
0.22 (0.30 - 0.16)
We subsequently investigated the oral administration of
ONOꢀ7300243 (17a) to determine its effect on rat IUP.
Compound 17a inhibited the LPAꢀinduced IUP increase in a
dose dependent manner (ID50 = 11.6 mg/kg p.o.) up to 1 h
after dosing (Figure 3A). Significant effects were observed at
10 and 30 mg/kg (p<0.05 vs. vehicle). We also assessed
whether or not this LPA1 antagonist influenced in blood
pressure in conscious rats (Figure 3B). ONOꢀ7300243 (17a)
(30 mg/kg, p.o.) led to a significant decrease in the IUP in
conscious rats without LPA stimulation compared with the
vehicle without affecting the mean blood pressure (MBP).
These results therefore suggested that the LPA1 receptor was
constantly activated to some extent in vivo, exhibiting LPA1
antagonist effects in normal rats without exogenous LPA
stimulation. For comparison, tamsulosin (α1 adrenoceptor
antagonist) which is used in clinical practice for the treatment
F
F
(0.23 - 0.15)
0.19
>1
*
-CH2-
17e
IC50 values were determined by nonlinear regression analysis of
the doseꢀresponse curves (5 points) generated using GraphPad
Prism ver.5.04 with 95% confidence intervals in parentheses.
Regarding section C, the replacement of the phenylpropyl
chain in 18a with a phenylethyl or phenylbutyl group gave
compounds 18b and 18c, respectively, which both showed
lower antagonist activities than 18a, indicating that the chain
length in critical to the activity (Table 3). Compounds 18b and
18c could not form a πꢀstacking interaction between the
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Table 4. Representative properties of ONOꢀ7300243 (17a),
18a, and 12g
1
2
3
4
5
17a
ONO-7300243
Cmpd
12g
18a
in vitro efficacy (ꢀM) a
6
7
8
9
LPA1
0.0035
(0.0050-0.0025)
0.79
0.16
(0.19-0.13)
0.10
(0.12-0.86)
LPA2
23
(96-5.4)
8.6
(10.3-7.2)
(1.9-0.33)
LPA3
>10
>10
-44
>10
-53
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
in vivo efficacy
Rat IUP (%) b
-88
physicochemical properties
477
574
461
MW
clogP
5.29
73
5.23
84
8.24
69
Solubility (ꢀM)
(pH6.8 buffer)
N.T. c
15.9 x 10-6
3.2 x 10-6
Caco2 (Papp)
Metabolic stability d
T1/2 (min)
Human MS
Rat MS
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<15
<15
a) IC50 values were determined by nonlinear regression analysis
of the doseꢀresponse curves (5 points) generated using GraphPad
Prism ver.5.04 with 95% confidence intervals. b) Maximal
inhibition rate of LPAꢀinduced increase of intraurethral pressure
(IUP) in anesthetized rats. Each compound (10 mg/kg) in 0.5%
methylcellulose was administered intraduodenally at 0 min and
LPA (300 ꢁg/kg) was injected intravenously at pre, 5, 15, 30 and
60 min. c) N.T. = not tested. d) 0.5 mg/mL, NADPH, MS:
microsomes.
of BPH,was tested in the same in vivo model (Figure 3C).
Tamsulosin significantly reduced IUP at 1 mg/kg oral
administration with the same potency for reducing IUP as
ONOꢀ7300243 (17a). This compound also led to a significant
reduction in MBP at the same dose.22 This difference in the
effect on blood pressure distinguishes LPA1 antagonists from
α1 adrenoceptor antagonists. Tamsulosin has been optimized
for once daily administration. In contrast, the results of a rat
pharmacokinetic study of ONOꢀ7300243 (17a) showed that
this material had a rapid clearance (CLtot = 15.9 mL/min/kg at
3 mg/kg i.v.) and a short halfꢀlife (0.3 h) (see Supplement, S35,
Table S1). The main goal of the lead optimization stage for
this compound would therefore involve making improvements
to its pharmacokinetic profile to yield a promising compound.
Figure 3. In vivo efficacy of ONOꢀ7300243 (17a)
(A) Dose responsibility of ONOꢀ7300243 (17a). The compound
was orally administered at each dose in conscious rats. After 60
min, LPA (300 ꢁg/kg) was injected intravenously and IUP was
measured in shortꢀterm anesthetized rats. (B, C) Change of IUP
and mean blood pressure (MBP) without LPA stimulation in
conscious rats. Vehicle, ONOꢀ7300243 (17a) or tamsulosin (α1
adrenoceptor antagonist) was orally administered at 0 min and
IUP and MBP were measured continuously for 60 min. The mean
pressure was calculated at 10 min intervals.
In conclusion, we have successfully obtained the orally
effective lead compound ONOꢀ7300243 (17a) as the result of
modification of section A and B of hit compound 7a. The oral
administration of compound 17a in rats led to a significant
reduction in IUP in a doseꢀdependent manner without
affecting MBP. When dosed at 30 mg/kg p.o., the potency of
ONOꢀ7300243 was the same as tamsulosin dosed at 1 mg/kg
p.o. The lead optimization of this compound will focus on
improving its pharmacokinetic profile and should lead to a
promising candidate for the treatment of BPH.
ASSOCIATED CONTENT
Supporting Information
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potent Autotaxin/ENPP2 inhibitor produces prolonged decreases in
plasma lysophosphatidic acid formation in vivo and regulates urethral
tension. PLOS ONE, 2014, 9, e93230.
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Experimental procedures, Pharmacokinetic parameters of
ONOꢀ7300243 (Table S1), LPA1 receptor antagonist assay, and
Van der Waals contact of Section C (Figure S1).
AUTHOR INFORMATION
Corresponding Author
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* Masahiko Terakado. Tel: +81-75-961-1151. Fax: +81-75-962-9314. E-mail:
terakado@ono.co.jp
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O
O
MeO
Me
N
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N
MeO
OMe
CO2H
HO2C
ONO-7300243
Lead compoound
HTS hit compound 7a
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LPA1: IC50 = 4.4 ꢀM
LPA1: IC50 = 0.16 ꢀM
LPA induced rat IUP model
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ID50 = 11.6 mg/kg p.o.
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