Discovery of 6-oxo-3 (2-phenylpyrazolo[1,5-α]pyridin-3-yl) 1(6H)- pyridazinebutanoic acid (FK 838): A novel non-xanthine adenosine A1 receptor antagonist with potent diuretic activity [1]

Full text of DOI:10.1021/jm980671w

©
Copyright 1999 by the American Chemical Society
Volume 42, Number 5
March 11, 1999
Communications to the Editor
Discover y of 6-Oxo-3-
2-p h en ylp yr a zolo[1,5-a ]p yr id in -3-yl)-
(6H)-p yr id a zin ebu ta n oic Acid (F K 838):
(
1
A Novel Non -Xa n th in e Ad en osin e A1
Recep tor An ta gon ist w ith P oten t
Diu r etic Activity
Atsushi Akahane,* Hirohito Katayama,
Takafumi Mitsunaga, Takeshi Kato,
Takayoshi Kinoshita, Yasuhiro Kita,
Takahiro Kusunoki, Takao Terai, Keizo Yoshida, and
Youichi Shiokawa
1
F igu r e 1. Structures of adenosine A antagonists 1 and 2.
Medicinal Chemistry Research Laboratories,
Fujisawa Pharmaceutical Company, Ltd., 1-6, 2-chome,
Kashima, Yodogawa-ku, Osaka 532-8514, J apan
Received November 30, 1998
In tr od u ction . Adenosine is a purine nucleoside that
is widely distributed throughout the body and exerts a
wide variety of physiological functions through interac-
1
tion with extracellular receptors. To date, four distinct
adenosine receptor subtypes (A1, A2A, A2B, and A3) have
2
been cloned and characterized pharmacologically. Nu-
merous adenosine receptor ligands have been synthe-
sized and studied as adenosine receptor agonists and
antagonists and have thus resulted in clinically exam-
ined compounds.3 Despite such efforts over several
decades, the only compound approved is adenosine itself,
which is currently used for the treatment and diagnosis
4
of cardiac arrhythmias and for the diagnosis of ischemic
5
heart diseases. In the field of adenosine antagonists,
perhaps the major reason adenosine ligands have not
succeeded in addressing significant medical need is the
poor bioavailability of hitherto described analogues,
mainly due to hydrophobicity and low solubility in
water. For this reason, it is highly desirable to develop
a selective, potent, and bioavailable non-xanthine ad-
enosine receptor antagonist.6
F igu r e 2. X-ray structure of 2.
thines in water is extremely low, due to greater hydro-
phobicity. Recently, we described the discovery of (E)-
(2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-
2-piperidineethanol (FK 453, 2; Figure 1), a novel non-
xanthine adenosine A1 receptor antagonist, as a diuretic
Recent reports have demonstrated that 1,3-dipropyl-
8
-cyclopentylxanthine (DPCPX, 1; Figure 1) and related
8
xanthines, which are potent and selective adenosine A1
receptor antagonists, have diuretic and saliuretic prop-
and renal vasodilator. Interestingly, 2 was originally
identified as a potent diuretic, and later the exact
mechanism of action was identified to be selective for
7
erties. However, the solubility of these dipropylxan-
1
0.1021/jm980671w CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/20/1999

7
80 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Communications to the Editor
F igu r e 3. Design of 3-heteroaryl-2-phenylpyrazolo[1,5-a]pyridines.
Sch em e 1a
Sch em e 2a
a
(a) ClCO2Et, pyridine; (b) air, t-BuOK, t-BuOH; (c) ClCO2Et,
pyridazine.
adenosine A1 receptor antagonism; i.e., 2 was not found
through in vitro receptor binding assay but through in
vivo assay. Nevertheless, 2 was extraordinarily potent
and highly selective for binding to the adenosine A1
receptor subtype in the receptor binding assay. The
pyrazolo[1,5-a]pyridine-based structure of 2 was com-
pletely different from known xanthine and non-xanthine
adenosine A1 receptor antagonists, and therefore 2 was
a structurally unique adenosine receptor antagonist.
Although 2 was a potent diuretic in several species,
including humans,9 the oral bioavailability of 2 was
relatively low due to a rapid first-pass effect in the liver
and to the poor solubility in water, which also resulted
in problems in the preparation of intravenous formula-
tions which are essential for the treatment of acute
a
(a) Concd H2SO4, Ac2O; (b) HCOCO2H‚H2O; (c) NH2NH2‚H2O;
(
d) RX or methyl acrylate, NaH or Triton B; (f) aq NaOH.
indispensable for potent diuretic activity (unpublished
results). Compounds in which the (E)-acryloyl moiety
was replaced by (Z)-acryloyl, propionyl, or propioloyl
were essentially inactive. Therefore, it was quite clear
that the conformation of the acryloyl part of 2 was very
important. The X-ray crystal structure of 2 (Figure 2)
clearly indicated that the (E)-acryloyl moiety adopted
the s-cis conformation. Furthermore, the double bond
of the acryloylamide of 2 was almost in the same plane
as the pyrazolo[1,5-a]pyridine ring (torsion angle of C7-
C8-C16-C17: -9°), and the carbonyl group (C18-O19)
and the double bond of the acryloyl moiety (C16-C17)
were slightly twisted (torsion angle of C16-C17-C18-
O19: -24°), while the phenyl ring was rotated 45°
clockwise to the pyrazolo[1,5-a]pyridine ring (C8-C9-
C10-C15). On the basis of these findings, we then
designed new compounds in which position 3 of the
2-phenylpyrazolo[1,5-a]pyridine was substituted by het-
eroaryl groups such as 4-pyridyl, 4-pyridazinyl, and
6-oxo-1(6H)-pyridazin-3-yl, in which the double bond
and carbonyl group of acryloyl moiety of 2 were mim-
icked by a ring system (Figure 3). These compounds
were predicted to be stable to light and to be potentially
more hydrophilic if suitable substituents were intro-
duced to the heteroaryl groups.
1
0
renal failure, a possible clinical indication for 2. In
addition, 2 was readily converted to the less active cis
isomer in solution due to a facile photochemical trans-
cis isomerization process.8
a
To overcome these problems and to obtain compounds
with more potent in vivo activity, we initiated a search
for a new series of pyrazolo[1,5-a]pyridine diuretics. In
this paper we describe the rational design, synthesis,
and pharmacological evaluation of a series of 3-het-
eroaryl-2-phenylpyrazolo[1,5-a]pyridines with an im-
proved pharmacokinetic profile, greater water solubility,
and superior in vivo potency.
Design . In structure-activity relationship (SAR)
studies of 2, the (E)-acryloyl moiety was found to be

Communications to the Editor
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5 781
Ta ble 1. Diuretic Activity in Rats and Clog P Value of 5, 7, 9, and 2
diuretic activity in ratsa
compd
R
clog Pb
dose (mg/kg)
vehicle
UV (mL/kg)
Na+ (µequiv/kg)
K+ (µequiv/kg)
5
4.10
10.8 ( 0.7
34.2 ( 0.4**
1750 ( 27
5110 ( 290**
405 ( 78
975 ( 8*
1
0
7
2.89
vehicle
18.5 ( 0.4
23.8 ( 2.3
29.5 ( 3.9
38.0 ( 2.1**
15.7
2000 ( 250
2800 ( 300
3770 ( 370*
5110 ( 150*
1670
427 ( 34
569 ( 49
667 ( 33**
907 ( 56**
449
1
3
1
.0
.2
0
c
9
2
2.95
3.24
vehicle
33.3 ( 3.9d
4640 ( 410d
826 ( 41
d
1
0
vehicle
0.32
16.3 ( 1.4
18.0 ( 1.0
24.6 ( 0.5**
31.9 ( 1.4**
44.4 ( 2.0**
2080 ( 190
2350 ( 160
3290 ( 190**
4110 ( 260**
5820 ( 200**
615 ( 85
727 ( 58
(FK453)
1
3
1
.0
.2
0
833 ( 10
831 ( 40
1070 ( 100*
a
After deprivation of food for 18 h, compounds suspended in 0.5% methyl cellulose solution were administered orally to saline (20
mL/kg, po)-loaded male Sprague-Dawley rats (n ) 3), and urine was collected for 6 h; see ref 8b for details. Values are expressed as
means ( SEM. *p < 0.05. **p < 0.01. UV: urine volume. b Calculated by MacLogP. c n ) 1. d Statistical evaluation was not performed.
Ch em istr y. Compounds 5 and 7 were prepared
according to the route shown in Scheme 1. The starting
material 3, which was obtained by a modification of the
reported method,11 was treated with ethyl chloroformate
and pyridine to afford dihydropyridine 4, which was
then converted to pyridine 5 using potassium tert-
butoxide in tert-butyl alcohol. Analogously, 7 was ob-
tained from the reaction of 3 with ethyl chloroformate
and pyridazine, followed by the treatment with tert-
butoxide in tert-butyl alcohol.
The diuretic activity and clog P values of pyridazinone
derivatives 10a -10d and 11-13 are summarized in
1
Table 2. Substitution at N of the pyridazinone was
tolerated for diuretic activity. Regardless of the variety
of substituents, all compounds in Table 2 increased
urine and sodium output at 10 mg/kg. Comparison of
clog P values showed that compounds containing func-
tional groups such as hydroxyl and carboxylic acid were
more hydrophilic than 2 or 10b. Carboxylic acids 11 and
12 had suitable clog P values (1.95 and 2.48) and potent
diuretic activity and were actually soluble in water, if
used as the sodium salt form. Both 11 and 12 increased
urine and sodium output in a dose-dependent manner.
The minimum effective doses of 11 and 12 in diuretic
activity were 3.2 and 0.1 mg/kg, respectively. 12 was
10 times more potent than 2, when comparing the
minimum effective dose.
Pyridazinone derivatives 9, 10a -10d , 11, 12, and 13
were prepared as shown in Scheme 2. Friedel-Crafts
reaction of 3 using acetic anhydride in the presence of
a catalytic amount of concentrated sulfuric acid afforded
8
, which was then treated with glyoxylic acid monohy-
drate. The intermediate adduct was cyclized with hy-
drazinemonohydrate to give pyridazinone 9. Alkylation
of 9 was performed by standard methods. For example,
To identify the mechanism of action of 12, receptor
binding assays for 1, 2, and 12 were performed using
rat and human A1 and rat A2A adenosine receptors
(Table 3). While affinity and selectivity of 1 and 2 for
the A1 adenosine receptor was potent and good, 12 was
less active and less selective for the A1 adenosine
receptor compared with 1 and 2. However, 12 still had
considerable affinity and selectivity for A1 adenosine
9
was alkylated with alkyl halides or methyl acrylate
in the presence of bases such as sodium hydride or
Triton B, to afford 10a -10g. Esters 10e-10g were
hydrolyzed with aqueous sodium hydroxide to give
carboxylic acids 11, 12, and 13, respectively.
Resu lts a n d Discu ssion . The diuretic activity of the
test compounds was evaluated orally in saline-loaded
rats (Tables 1 and 2). As shown in Table 1, 5, 7, and 9
increased urine and sodium output at 10 mg/kg, and
the efficacy of these compounds in diuresis and natri-
uresis was the same as that of 2 (2-3-fold of each control
value). These results indicated that the acryloyl moiety
of 2, which was very important for diuretic activity,
could be changed to a heteroaryl group. In a dose-
response study, 7 was less active than 2. The minimum
effective doses of 2 and 7 in diuretic activity were 1.0
and 3.2 mg/kg, respectively. We compared the clog P
values of the compounds shown in Table 1 as a param-
eter of hydrophobicity. The order of hydrophobicity was
8
d
receptors. Compound 12, as well as 1 and 2, also
+
inhibited the Na transport in rabbit proximal convo-
luted tubule in vitro via adenosine A1 receptor (unpub-
lished results). These results suggest that the diuretic
activity of 12 results from adenosine A1 receptor an-
tagonism. To clarify the discrepancy between in vitro
and in vivo activity, i.e., 12 was more potent than 2 in
diuretic activity in rats, but 2 was more potent than 12
at the adenosine A1 receptor, the solubility of 2 and 12
in water at 37 °C and the oral bioavailabilities of 2 and
12 in rats were determined (Table 3). The solubility of
2 in water was only 11.9 µg/mL, while 12 had greater
solubility (10 mg/mL) in water, when the sodium salt
was used. Similarly, the oral bioavailability of 2 in rats
was 8.8% and that of 12 was 78% (free acid) and 100%
5
> 2 > 9 > 7 (Table 1). After consideration of the ease
of synthesis of analogues, we selected 9 as a new lead
and started a lead optimization study.

7
82 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Communications to the Editor
Ta ble 2. Diuretic Activity in Rats and Clog P Value of 10a -10d , 11-13, and 2
diuretic activity in ratsa
compd
R
clog Pb
dose (mg/kg)
vehiclec
UV (mL/kg)
15.7
30.0 ( 3.2
15.7
Na+ (µequiv/kg)
K+ (µequiv/kg)
1
1
1
1
1
0a
Me
2.88
1660
449
891 ( 78
449
d
d
d
1
0
4870 ( 290
c
0b
0c
0d
1
n-Pr
3.93
1.42
1.95
1.95
vehicle
1660
36.8 ( 2.9d
19.5 ( 1.9
40.4 ( 1.1*
17.3 ( 1.2
37.9 ( 0.1**
15.2 ( 1.3
19.1 ( 0.9
28.1 ( 1.8**
31.4 ( 2.1**
16.2 ( 1.1
15.6 ( 1.1
26.4 ( 2.6*
35.8 ( 0.6**
38.6 ( 2.9**
18.8 ( 2.8
36.3 ( 1.7*
16.3 ( 1.4
18.0 ( 1.0
24.6 ( 0.5**
31.9 ( 1.4**
44.4 ( 2.0**
5510 ( 80d
2150 ( 11
972 ( 19
d
1
0
(CH2)2OH
(CH2)3OH
(CH2)2CO2H
vehicle
590 ( 37
942 ( 20*
615 ( 2
1
0
5930 ( 440
2090 ( 110
5160 ( 67**
2850 ( 300
3350 ( 120
4860 ( 310**
5260 ( 420**
2280 ( 160
2390 ( 150
3860 ( 240**
5260 ( 160**
5680 ( 220**
2190 ( 170
4510 ( 330*
2080 ( 190
2350 ( 160
3290 ( 190**
4110 ( 260**
5820 ( 200**
vehicle
1
0
964 ( 157
621 ( 52
790 ( 53
904 ( 42*
901 ( 58*
566 ( 64
657 ( 62
818 ( 52*
967 ( 15**
1150 ( 49**
502 ( 29
977 ( 135
615 ( 85
727 ( 58
833 ( 10
831 ( 40
1070 ( 100*
vehicle
e
1
3
1
.0
.2e
e
0
1
(
2
(CH2)3CO2H
(CH2)4CO2H
2.48
vehicle
e
FK 838)
0.032
e
0
1
1
.1
.0
0
e
e
1
2
3
3.00
3.24
vehicle
e
1
0
vehicle
0.32
(
FK453)
1
3
1
.0
.2
0
a-d
See corresponding footnotes in Table 1. e Sodium salt was used.
Ta ble 3. Binding Affinities of 12, 2, and 1 at A1 and A2A
Adenosine Receptors and Pharmacokinetic Profiles of 12 and 2
acid moiety of 12 corresponds to the 2-piperidineethanol
moiety of 2. Further study will be necessary to improve
in vitro receptor binding affinity and selectivity of 12,
by modification of the butanoic acid moiety.
adenosine receptor binding
solubility
a
(pKi)
in water
b
BA (%)c
78
compd
A1
A2A
(µg/mL)
In summary, based upon an X-ray crystal structure
of 2 (FK 453), we designed and synthesized a new series
of pyrazolo[1,5-a]pyridines, in which heterocyclic groups
were introduced instead of the acryloylamide of 2.
Compound 12 displayed the most potent diuretic activ-
ity and was a potent and selective adenosine A1 receptor
antagonist with good oral availability and solubility in
water. Among the many adenosine A1 receptor antago-
nists reported, 12 can be classified as the first of a new
generation of adenosine A1 receptor antagonists, which
are useful for the treatment of diseases such as hyper-
tension and renal failure. Compond 12 (FK 838) is
undergoing phase 2 clinical trials as a diuretic antihy-
pertensive agent. Further investigations of the SAR and
optimization of this class of adenosine A1 receptor
antagonist will be reported subsequently.
1
2
1
2 (FK 838)
8.18 ( 0.09
5.92 ( 0.03
10000d
(
100)d
(FK 453)
9.31 ( 0.09
9.31 ( 0.76)
9.55 ( 0.04
5.90 ( 0.16
11.9
8.8
e
(
(DPCPX)
6.82 ( 0.05
a
3
A1 binding was carried out with [ H]DPCPX in rat cortical
3
membranes, and A2A binding was carried out with [ H]CGS 21680
in rat striatal membranes. Values are means ( 95% confidence
limits determined from at least three independent experiments.
See ref 12 for details. Data from ref 12. Solubility at 37 °C. c Oral
bioavailability in fasted rats. Compounds were suspended in 0.5%
methyl cellulose solution, and 3.2 mg/kg 12 and 10 mg/kg 2 were
b
administered orally (n ) 3-4). d Sodium salt was used. e Data in
parentheses is for A1 receptors from human cortical membranes;
see ref 12.
(sodium salt). These results can clearly explain the
above discrepancy. 12 was more hydrophilic and soluble
in water than 2, and the improved oral bioavailability
of 12 resulted in more potent diuretic activity, despite
relatively low affinity for adenosine A1 receptors. Due
to the greater solubility in water, 12 can be used not
only orally but also intravenously. Furthermore, 12 was
stable to light in solution.
Ack n ow led gm en t. We thank Dr. Kazuo Sakane
and Dr. David Barrett of Medicinal Chemistry Research
Laboratories of Fujisawa Pharmaceutical Co., Ltd. for
helpful suggestions.
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3
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(
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J M980671W