Dioxotriazine derivatives as a new class of P2X3 receptor antagonists: Identification of a lead and initial SAR studies

Article abstract of DOI:10.1016/j.bmcl.2021.127833

P2X₃ receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X₃ receptor antagonists for the treatment of chronic pain or cough. To identify

Full text of DOI:10.1016/j.bmcl.2021.127833

Bioorg. Med. Chem. Lett. 37 (2021) 127833
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Dioxotriazine derivatives as a new class of P2X3 receptor antagonists:
Identification of a lead and initial SAR studies
,
,
Hiroyuki Kaia *, Tohru Horiguchia *, Takayuki Kameyamab, Kentaro Asahia, Takeshi Endohc,
Sae Jikiharad, Tsuyoshi Hasegawae, Satoru Tanakaa, Azusa Nozua, Chie Takeyamae,
Maki Tomarie, Fumiyo Takahashif, Naomi Tamurag, Shigenori Yagia, Tetsuji Itohh,
Yasuyoshi Isoui
a Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
b Corporate Social Responsibility Department, Shionogi & Co., Ltd., 12F, Hankyu Terminal Bldg., 1-4 Shibata 1-chome, Kita-ku, Osaka 530-0012, Japan
c Shionogi Administration Service Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
d Corporate Planning Department, Shionogi & Co., Ltd., 1-8, Doshomachi 3-chome, Chuo-ku, Osaka 541-0045, Japan
e Shionogi TechnoAdvance Research & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan
f Laboratory for Innovative Therapy Research & Disease Research, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan
g Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan
h Disease Care Strategy Department, Shionogi & Co., Ltd., 2F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan
i CMC R&D Division, Shionogi & Co., Ltd., 1-3, Kuiseterajima 2-chome, Amagasaki, Hyogo 660-0813, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords:
P2X3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several
clinical trials are being conducted with P2X3 receptor antagonists for the treatment of chronic pain or cough. To
identify a P2X3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine de-
rivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead com-
pound 1 which had a moderate inhibitory effect on P2X3 receptors (IC50, 128 nM). Further improvement of the
potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X3 IC50, 16.1 nM;
P2X2/3 IC50, 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in
the rat partial sciatic nerve ligation model of neuropathic pain (ED50, 3.1 mg/kg).
Purinergic receptors
Ion channels
P2X3 receptor antagonists
Dioxotriazine derivatives
Pain
P2X3 receptor, a ligand-gated ion channel activated by ATP, is
mainly localized in the peripheral sensory neuron.1 P2X3 receptor an-
tagonists (Fig. 1) reportedly show analgesic effects in neuropathic and
inflammatory pain models.2 Therefore, many P2X3 receptor antagonists
are targets in the development of analgesics.3 Among them, gefapixant
showed alleviation of interstitial cystitis/bladder pain syndrome (IC/
BPS) in a Phase 2 clinical trial. Additionally, gefapixant showed allevi-
ation of refractory chronic cough in a Phase 2b clinical trial. Thus, ex-
pectations are high for the utility of P2X3 receptor antagonists in the
treatment of various diseases.4
suspended due to a potential risk of drug-drug interactions.
We reexamined the compounds obtained by HTS to explore novel hit
compounds (Fig. 2. A). Among them, based on a chemist’s flash of
inspiration of the similarity between dioxotriazines and RO-3, a known
P2X3 antagonist,8 we reevaluated dioxotriazines and found that they
exhibit weak activity. One dioxotriazine was selected as a hit compound
(IC50, 1200 nM). The hit to lead SAR was done using parallel synthesis
(Fig. 2. B), and compound 1 with improved potency (IC50, 128 nM) and a
modest PK profile on rat (Clt, 23.9 mL/min/kg; BA, 25.2%) was selected
as a lead compound.
We previously reported on pyrrolinone and pyrropyrazolone de-
rivatives (Figure 1.) as a new class of selective P2X3 antagonists,5–7
which were derivatized from screening hits from the Shionogi com-
pound library. Even though the selected compounds showed high oral
absorbabilities and potent analgesic effects, clinical developments were
In this paper, we report further SAR study from compound 1, which
led to a new class of selective P2X3 antagonists, which showed improved
oral absorbabilities and potent analgesic effects.
Synthesis of compounds with various linkers at position 6 are sum-
marized in Scheme 1–4.9
* Corresponding authors.
E-mail addresses: hiroyuki.kai@shionogi.co.jp (H. Kai), tooru.horiguchi@shionogi.co.jp (T. Horiguchi).
https://doi.org/10.1016/j.bmcl.2021.127833
Received 12 October 2020; Received in revised form 22 January 2021; Accepted 25 January 2021
Available online 2 February 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

H. Kai et al.
Bioorganic & Medicinal Chemistry Letters 37 (2021) 127833
Fig. 1. Classical P2X3 receptor antagonists and Shionogi’s pyrrolinone and pyrropyrazolone.
Fig. 2. Exploration of a novel hit compound and hit to lead SAR of dioxotriazines A. Dioxotriazine was selected as a hit compound, based on its structural
resemblance to Ro-3B. Parallel synthesis of dioxotriazines gave lead compound 1 with improved potency and a modest PK profile on rat.
2

H. Kai et al.
Bioorganic & Medicinal Chemistry Letters 37 (2021) 127833
Scheme 1. Reagents and conditions for the synthesis of compound 1: (a) i-PrNCO, DBU, DMF, 0 ◦C, 4 h then CDI, DBU, rt, overnight, 72%; (b) 4-Cl-PhCH2Br, K2CO3,
MeCN, reflux, 1.5 h, 100%; (c) 4-i-PrOPhNH2, AcOH, 100 ◦C, 9 h, 76%.
Scheme 2. Reagents and conditions for the synthesis of compound 9: (a) MeI, MeOH, rt, 5 h; (b) ClCONCO, DIPEA, CH2Cl2, rt, 1 h, 58%; (c) i-PrBr, t-BuOK, DMF,
55 ◦C, 17 h, 61%; (d) microwave, AcONH4, t-BuOH, 200 ◦C, 25 min, 69%; (e) 4-i-PrO-PhCOCl, Et3N, DMF, rt, 4 h, 49%.
Scheme 3. Reagents and conditions for the synthesis of compound 13: (a) NH4Cl, AlMe3, PhMe, 80 ◦C, overnight, 94%; (b) EtNCO, DBU, DMA, rt, 1 h then CDI, DBU,
rt, 3 h, 58%; (c) 4-Cl-PhCH2Br, DIPEA, DMA, 60 ◦C, 3 h, 39%.
Scheme 4. Reagents and conditions for the synthesis of compound 16: (a) THPO(CH2)2OH, PPh3, DIAD, THF, rt, 3 h, 78%; (b) microwave, 4-i-PrO-PhOH, Pyridine,
180 ◦C, 2 h, 45%; (c) PPTS, MeOH/CH2Cl2, rt, 4 h, 48%.
Scheme 5. Reagents and conditions for the synthesis of compound 20: (a) 4-Cl-PhCH2Br, NaH, LiBr, DMF, rt, overnight, 42%; (b) Br(CH2)3CO2Me, NaH, DMF, 50 ◦C,
1 h, 88%; (c) 3-Cl-4-i-PrO-PhNH2, Pd(OAc)2, xantphos, Cs2CO3, Dioxane, 100 ◦C, 1 h; (d) 1 Mꢀ LiOH aq, MeOH/THF, rt, 4 h, 67%.
Scheme 1 shows the synthesis of compound 1. Treatment of S-eth-
ylisothiourea hydrobromide 2 with isopropyl isocyanate and 1,l′-car-
bonyldiimidazole in the presence of DBU in DMF afforded 6-(ethylthio)-
triazinedione 3.10 Alkylation of 3 with 4-chlorobenzybromide and
K2CO3 furnished intermediate 4. The ethylthio group of 4 was
substituted by the 4-isopropoxyanilino group by treatment with 4-iso-
propoxyaniline in AcOH at 100 ◦C to obtain compound 1.
intermediate 7, a homolog of 4. Nucleophilic substitution of the 6-meth-
ylthio group of 7 with ammonia required MW irradiation at 200 ◦C to
give amine 8,12 which was coupled with 4-isopropoxy-benzoyl chloride
to afford target compound 9.
We also prepared 6-benzyl derivative 13 by the method shown in
Scheme 3. Reaction of 2-(4-isopropoxyphenyl)acetonitrile 10 with
NH4Cl in the presence of AlMe3 furnished amidine 11.13 Treatment of 11
with EtNCO afforded 6-benzyltriazine 12, which is benzylated at posi-
tion 1, to give the target 6-benzyl derivative 13.
6-Benzeamide derivative 9 was prepared as depicted in Scheme 2.
Methylation of 1-(4-chlorobenzyl)thiourea 5, followed by treatment
with ClCONCO gave triazine 6.11 Isopropylation at position 3 afforded
6-Aryloxy triazine derivative14 16 (Scheme 4) was prepared from the
3

H. Kai et al.
Bioorganic & Medicinal Chemistry Letters 37 (2021) 127833
Scheme 6. Preparation of 22a and 22b: (a) 4-Cl-PhCH2Br, DIPEA, CH2Cl2, rt, overnight, 22a (70%); (b) 4-Cl-PhCH2Br, K2CO3, DMF, rt, overnight, 22b (39%), 22c
(49%). Preparation of compound 26: (c) NBS, CH2Cl2, reflux, 2 h, 71%; (d) [ (E)-2- (Ethoxycarbonyl)vinyl]boronic acid, pinacol ester, PdCl2 (dtbpf), K2CO3, THF,
reflux, 2.5 h, 90%; (e) 3-Cl-4-i-PrO-PhNH2, AcOH, t-BuOH, reflux, overnight, 87%; (f) H2, 5% Pt/C sulfided, CHCl3/DMF, rt, 4.5 h; (g) 1 Mꢀ LiOH aq, EtOH, rt, 4.5 h,
33%. Preparation of compound 30: (h) 4-Cl-PhCH2Br, K2CO3, DMF, rt, overnight; (i) NBS, CH2Cl2, rt, 2.5 h, 34%; (i) [ (E)-2- (Ethoxycarbonyl)vinyl]boronic acid,
pinacol ester, PdCl2 (dtbpf), 2 Mꢀ K2CO3 aq, THF, reflux, 4 h, 55%; (j) 3-Cl-4-i-PrO-PhNH2, AcOH, t-BuOH, reflux, 2 days, 44%; (k) H2, 5% Pt/C sulfided, CHCl3/DMF,
rt, 4.5 h; (l) 1 Mꢀ LiOH aq, EtOH, rt, 4.5 h, 35%.
Scheme 7. Reagents and conditions for the synthesis of compound 35: (a) 3-Cl-4-i-PrO-PhNH2, AcOH, t-BuOH, reflux, overnight, 84%; (b) POCl3, 50 ◦C, 2 h; (c) [ (E)-
2- (Ethoxycarbonyl)vinyl]boronic acid, pinacol ester, PdCl2 (dtbpf), 1 Mꢀ K2CO3 aq, THF, reflux, 7 h, 30%; (d) H2, 10% Pt/C, MeOH, rt, 0.5 h; (e) 1 Mꢀ LiOH aq,
EtOH, rt, 4.5 h, 9%.
intermediate 6. Mitsunobu reaction of 6 with THP-O(CH2)2OH gave
intermediate 14, and the 6-methio group of 14 was substituted with an
aryloxy moiety under MW irradiation in pyridine at 180 ◦C to give in-
termediate 15. Deprotection of the THP group of 14 with PPTS in MeOH
yielded the target 16
hydrolysis of the Et ester, furnished the target 26.
6-Oxo-1,6-dihydropyrimidine analog 30 was prepared from the 22b
by a method very similar to that for preparation of the 4-oxo-1,4-dihy-
dropyrimidine analog 26; however, nucleophilic substitution of the 6-
methylthio group of 28 with aniline required long hours and resulted
in a poor yield relative to that of 24.
Synthesis of center ring analogs are shown in Schemes 5–7.
Benzylation and subsequent alkylation of 6-chlorouracil 17 (Scheme
5) afforded intermediate 18.15 Pd catalysis coupling of 18 and aniline,16
followed by alkaline hydrolysis of the methyl ester 19 yielded the uracil
analog 20.
4-Alkyltriazine 35 (Scheme 7) was prepared from triazine 31.
Chlorination of 32 using POCl3 afforded the 4-chloride 33, which was
converted to the target 35 by methods very similar to those in Schemes
6.
4-Oxo-1,4-dihydropyrimidine analog 26 and 6-Oxo-1,6-dihydropyr-
imidine analog 30 (Scheme 6) were prepared from a same starting
material, 2-(methylthio)pyrimidin-4(3H)-one 21. Benzylation of 21
with chlorobenzylbromide in the presence of DIPEA in CH2Cl2, followed
by extraction and trituration of the product with EtOAc afforded 1-(4-
To evaluate the P2X receptors antagonistic activities of all com-
pounds, IC50 was calculated using stably expressed C6BU-1 cells trans-
fected with the human P2X1,
,
,
receptor genes, HEK-293 cells
4
3
transfected with human P2X7 r2eceptor gene, or transiently expressed
C6Bu-1 cell transfected with P2X2 and P2X3 receptor genes.
chlorobenzyl)-2-(methylthio)pyrimidin-4(1H)-one 22a as
a
major
Table 1 shows the substituent effects of dioxotriazine derivatives on
P2X3 receptor antagonistic activity. First, the effect of the linker (X) at
position 6 on the triazine ring was investigated, and the NH moiety was
found to be crucial for the potency. The IC50 value of compounds 1, 36,
and 37 were 128 nM, 149 nM, and 83 nM, respectively, while other
product (70%), while benzylation of 21 in the presence of K2CO3 in DMF
afforded the isomers (22b, 39%) and (22c, 49%) mainly. Subsequent
bromination of the 22a afforded the bromide 23. Suzuki coupling of 23
with vinyl boronic acid pinacol ester gave intermediate 24. Nucleophilic
substitution of the 6-methylthio group of 24 with aniline proceeded in a
similar manner to the triazine derivative 4, which afforded intermediate
25. Catalytic hydrogenation of the olefin 25, followed by alkaline
linkers (9: CONH, 13: CH2, 16: O) greatly reduced the potency (IC50
>
1000 nM).
For substituents on the phenyl group (R1), compared with the 4-i-PrO
4

H. Kai et al.
Bioorganic & Medicinal Chemistry Letters 37 (2021) 127833
Table 1
Table 2
SAR study of substituents X, R2 and A.
SAR study of substituents R2.
Compound
X
R1
A
R2
IC50
(nM) a
1
NH
CONH
NH
CH2
NH
O
4-i-PrO
4-i-PrO
4-i-PrO
4-i-PrO
4-i-PrO
4-i-PrO
3-CF3
4-
4-Cl-PhCH2
4-Cl-PhCH2
4-Cl-PhCH2
4-Cl-PhCH2
4-Cl-PhCH2
4-Cl-PhCH2
4-Cl-PhCH2
4-Cl-PhCH2
i-Pr
128
9
i-Pr
>1000
149
Compound
R2
IC50
Solubility a
Microsomal stab. (%)b
36
13
37
16
38
39
Et
Et
>1000
83
(nM)
(μ
M)
Human
Rat
(CH2)2OH
(CH2)2OH
i-Pr
42
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
i-Pr
45
415
38
13
48
93
9.1
176
38
14
18
34
11
629
66
78
46
27
ND
>50
10
36
78
86
36
21
68
59
0
49
54
42
35
1
>3000
389
H
NH
NH
Et
i-Pr
420
Pr
1
MeOCO
4-HOCO
4-i-
CH2Ph
ND
19
40
41
NH
NH
4-Cl-PhCH2
4-Cl-PhCH2
i-Pr
i-Pr
>3000
CH2CN
41
30
2
520
(CH2)2CN
COMe
23
PrNHCO
3-F-4-i-
PrO
8
42
43
44
45
46
47
NH
NH
NH
NH
NH
NH
4-Cl-PhCH2
4-Cl-PhCH2
4-Cl-PhCH2
4-Cl-PhCH2
H
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
45
(CH2)2OH
(CH2)3OH
(CH2)4OH
(CH2)2NHAc
(CH2)3NHAc
CH2COOH
(CH2)2COOH
(CH2)3COOH
(CH2)2CONH2
(CH2)2CONHMe
>50
>50
20
92
82
59
45
47
99
92
106
94
86
60
29
36
1
3-Cl-4-i-
PrO
31
>50
>50
>50
>50
>50
30
3-Cl-4-
MeO
450
953
>3000
144
15
97
99
103
61
30
3-Cl-4-
PhO
3-F-4-i-
PrO
>50
3-F-4-i-
PrO
ND: not detected.
aSolubilities were measured in sodium phosphate buffer (pH 6.8, 10 mmol)
containing 1% DMSO.
48
49
50
51
52
53
NH
NH
NH
NH
NH
NH
3-F-4-i-
PrO
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
>3000
>3000
>3000
>3000
>3000
>3000
bPercent of compound remaining after 30 min incubation with human (or rat)
liver microsomes (0.5 mg protein/mL) at 37 ◦C with or without NADPH
generating system.
3-F-4-i-
PrO
3-F-4-i-
PrO
4-MeO-Ph
4-Cl-Ph
3-F-4-i-
PrO
3-F-4-i-
PrO
Me2NCOCH2
be preferred for the potency. Ethyl was slightly more potent, and propyl
was 3 times more potent than isopropyl (42 vs 55, 56). Benzyl was
equipotent to isopropyl (42 vs 57), which indicates a wider space
around R2. Reduced potency was noted with a relatively short polar
group, e.g., acetyl directly connected to the nitrogen atom, and also CN
and COOH with one carbon linkage (CH2) (60, 58, 66). On the other
hand, long polar groups (CN, OH, NHAc, COOH, CONH2, CONHMe) at
the end of chains longer than two carbons (CH2CH2, CH2CH2CH2) all led
to potent compounds (59, 61, 62, 63, 64, 65, 67, 68, 70). The fact that
both lipophilic and hydrophilic groups were tolerated suggests that R2
may exist in the solvent-exposed surface area of the protein. Among
those investigated, the carboxylic acids (67, 68) were slightly less potent
than the other analogs, but they were more soluble and showed better
stabilities in both human and rat microsomes.
3-F-4-i-
PrO
a) IC50 was calculated using a stably expressed cell line (C6BU-1 cell) transfected
with the human P2X3 gene.
(1), polar functional groups such as COOMe (39), COOH (40) and
CONH-i-Pr (41) considerably reduced the potency, while introduction of
F (42) or Cl (43) at position 3 on the 4-i-PrO-Ar of compound 1 improved
the potency 3 to 4 times over compound 1.
For substituents at position 1 (A), only benzyl (42) and its isostere
thiophen (47) were potent, with others showing loss of the potency; the
unsubstituted (46), alkyls (48 and 49), phenyls (50 and 51), and amides
(52, 53) showed no activity. This indicates that hydrophobicity and the
length of the substituent are both necessary for the potency.
Interestingly, other center ring systems (B) were also tolerated (20,
26, 30, Table 3), and uracil was almost equipotent to triazine (20 vs 72).
Also, even triazine 35 displayed modest potency in spite of the different
orientation of the R2 group.
Next, we substituted an isopropyl moiety (R2) of compound 42 to
examine the potency, solubility and stability on human and rat micro-
somes (Table 2). Removal of isopropyl to give the unsubstituted 54
decreased the potency to 1/10 (42 vs 54), and thus substitutions seem to
All tested ring analogs showed high oral absorbability (71, 72, 20,
26), and triazine 72 with propanoic acid (n = 2, –CH2CH2COOH) at
position 3 displayed the best potency and the highest stability in rat.
With triazine and uracil derivatives of high activity in hand,
5

H. Kai et al.
Bioorganic & Medicinal Chemistry Letters 37 (2021) 127833
optimization of the R1–R4 moieties was carried out, focusing on the
polar R2 groups, especially carboxylic acid analogs due to their better
solubilities and stabilities (Fig. 3.).
Table 3
Among those examined, compounds 73 and 74 were selected for
further development because of their strong antagonist activity and
well-balanced ADME profiles (Table 4). Compounds 73 and 74 showed
better P2X3 selectivity over P2X2/3 than Ro-51.17 Both 73 and 74 were
more soluble in a neutral buffer JP2 (pH 6.8) than an acidic buffer JP1
(pH 1.2) probably due to their acidic nature attributed to the carboxylic
moieties. Compound 73 and 74 did not inhibit five major species of CYP
enzymes, which indicates their low risk of drug-drug interactions.
The selected compounds 73 and 74 showed good PK profiles and
demonstrated a strong analgesic effect on oral administration against
allodynia in the rat partial sciatic nerve ligation model of neuropathic
pain. The analgesic activity of compounds 73 (ED50: 4.1 mg/kg) and 74
(ED50: 3.1 mg/kg) were more potent than that of Ro-51 (ED50 : >10 mg/
kg).18
Effects of center ring systems (B).
Compound
B
n
IC50
CLt (ml/min/
kg) b
t1/2 (hr)
BA(%)
b
b
(nM)
71
72
1
2
20
13
1.7
0.5
2.1
6.0
71.2
43.2
20
26
2
1
34
2.1
8.3
2.2
1.8
61.5
79.9
Unfortunately, clinical development of compounds 73 and 74 was
suspended due to the predicted high dose in humans. Although not
selected for clinical development, these compounds were evaluated
from various aspects as tool compounds.
152
In conclusion, a new hit compound was identified by focusing on
dioxotriazines in reexamination of the compounds obtained by HTS of
the Shionogi compound library. The hit to lead SAR was performed by
using parallel synthesis to find lead compound 1. Replacement of the
center ring part (B) did not cause loss of potency, and among them,
triazine and uracil types showed high potency. The point of modification
was the R2 substituent at position 3 on the triazine ring where the polar
groups are expected to be effective for improvement of ADME and
physical properties. As a result of lead optimization, compounds 73 and
74 were selected for their high P2X3 selectivity, oral absorbability and
strong analgesic efficacy.
30
35
1
1
219
614
NT
NT
NT
NT
NT
NT
CLt: total clearance; t1/2: half-life; BA: oral bioavailability; NT: not tested.
aAll compounds were administered at 0.5 mg/kg iv and 1.0 mg/kg po.
Compounds were administered as a mixture of three to five compounds.
Fig. 3. Optimization of triazines and uracils High potent triazines and uracils were optimized on R1, R2, R3, and R4. Polar R２substituents were designed due to their
good solubility and stability. 73 and 74 were nominated for further evaluation.
6

H. Kai et al.
Bioorganic & Medicinal Chemistry Letters 37 (2021) 127833
Table 4
Biological tests of selected compounds.
Compound
In vitro activity IC50 (nM)
Solubilitya
JP1
(
μ
g/mL)
CYP inhibition IC50
(μ
M)
2C19
P2X3
P2X2/3
P2X1
P2X2
P2X4
P2X7
JP2
1A2
2C9
2D6
3A4
73
30.3
16.1
6.3
2366
2931
44.9
all: >30000
all: >30000
all: >10000
< 0.1
0.3
6.0
all: >20
all: >20
NT
74
169
Ro-51
NT
Compound
Rat pharmacokinetics (iv, 1 mg/kg; po, 3 mg/kg)
Analgesic effectsb
ED50 (mg/kg)
Clt (mL/min/kg)
T1/2 (h)
AUC (po)(ng hr/mL)
Cmax (po)(ng/mL)
BA (%)
fu (%)
Emax % (mg/kg)
73
3.0
2.7
9.6
1.6
1.1
6990
14,300
369
1260
1610
118
47.3
71.8
30.3
1.0
0.9
7.4
4.1
41% (10)
40% (10)
36% (100)
74
3.1
Ro-51
42.0
>10
a
JP1 (pH 1.2) measured in 1st Fluid for dissolution test and JP2 (pH 6.8) in 2nd Fluid for dissolution test in THE JAPANESE PHARMACOPOEIA.19
b
Rat Seltzer model: Allodynia (von Frey).
8
9
Carter DS, Alam M, Cai H, et al. Bioorg Med Chem Lett. 2009;19:1628.
For more information on chemistry and biology, please refer to supporting
information and our patent; a) Kai, H.; Kameyama, T.; Horiguchi, T.; Asahi, K.;
Endoh, T.; Fujii, Y.; Shintani, T.; Nakamura, K.; Matsumoto, S.; Hasegawa, T.;
Oohara, M.; Tada, Y.; Maki, T.; Iida, A., US patent US 2013/0172317 A1 2013., b)
Kai, H.; Endoh, T.; Matsumoto, S.; Asahi, K.; Horiguchi, T., US patent US 2013/
0225596 A1 2013.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
10 a) Fuchs, Julius, J;. Lin.Kang. US1976/3951971,. b)Masami, Ogawa.; Takashi,
Matsui.; Junzo Tobitsuka, and Hiroko, Kitamkura. Agric. biol. chem., 1980, 44 (9),
2161-2167.
Appendix A. Supplementary data
11 Congiu, Cenzo; Onnis, Valentina; Deplano, Alessandro; Salvadori, Severo; Marconi,
Veronica; Maftei, Daniela; Negri, Lucia; Lattanzi, Roberta; Balboni, Gianfranco., Eur.
J. Med. Chem., 2014, 81, 334 – 340.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127833.
12 Kong Kah-Hoe, Tan Chong-Kiat, Lam Yulin. J Comb Chem. 2009;11(6):1050–1060.
13 Aroyan, et al. Arm Khim Zh. 1967;20(4):314–321.
References
14 Munetaka, Kushima. JP2017/81832.
15 El-Emam Ali A, Massoud Mohamed AM, El-Bendary Eman R, El-Sayed Magda A.
BULL Korean Chem Soc. 2004;25(7):991–996.
1
2
3
4
5
6
7
Anthony PF. Purinergic Signall. 2012;8:S3.
Gum RG, Wakefield B, Jarvis MF. Purinergic Signall. 2012;8:S41.
Marucci G, Ben DD, Buccioni M, et al. Exp Op Ther Pat. 2019;19:943.
Abdulgawi R, Dockry R, Holt K, et al. Lancet. 2015;385:1198.
16 James P. Schulte II.; Scott R. Tweedie., Synlett. 2007, 2331-2336.
17 Jahangir A, Alam M, Carter DS, et al. Bioorg Med Chem Lett. 2009;19:1632.
18 S.R. Chaplan.; F.W. Bach.; J.W. Pogrel.; J.M. Chung, T.L., J. Neurosci. Methods,
1994, 53, 55-63.
Tobinaga H, Kameyama T, Oohara M, et al. Bioorg Med Chem Lett. 2018;28:2338.
Tobinaga H, Kameyama T, Asahi K, et al. Bioorg Med Chem Lett. 2019;29:688.
Tobinaga, H.; Kameyama, T.; Asahi, K.; Horiguchi, T.; Oohara, M.; Taoda, Y.; Hata,
K.; Tada,Y.; Hasegawa, T.; Kurihara, N.; Kanda, Y.; Yagi, S.; Tomari, M.; Tanaka, Y.;
Takahashi, F.; Taniguchi, E.; Takahara, Y.; Shimada, S.; Takeyama, C.; Yamamoto, S.;
Shinohara, S.; Kai, H., Bioorg. Med. Chem. Lett., in press.
19 Japanese Pharmacopoeia (JP) is established and published to regulate the properties
and quality of drugs by the Minister of Health, Labour and Welfare of Japan; Please
refer to: https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/0000066597.html.
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