Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion

Article abstract of DOI:10.1016/j.bmc.2017.04.034

With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger C?log?P value (1.95), larger log?D value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action.

Full text of DOI:10.1016/j.bmc.2017.04.034

Accepted Manuscript
Exploration of pyrrole derivatives to find an effective potassium-competitive
acid blocker with moderately long-lasting suppression of gastric acid secretion
Haruyuki Nishida, Ikuo Fujimori, Yasuyoshi Arikawa, Keizo Hirase, Koji Ono,
Kazuo Nakai, Nobuhiro Inatomi, Yasunobu Hori, Jun Matsukawa, Yasushi
Fujioka, Akio Imanishi, Hideo Fukui, Fumio Itoh
PII:
S0968-0896(17)30547-3
DOI:
http://dx.doi.org/10.1016/j.bmc.2017.04.034
BMC 13704
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 March 2017
24 April 2017
26 April 2017
Please cite this article as: Nishida, H., Fujimori, I., Arikawa, Y., Hirase, K., Ono, K., Nakai, K., Inatomi, N., Hori,
Y., Matsukawa, J., Fujioka, Y., Imanishi, A., Fukui, H., Itoh, F., Exploration of pyrrole derivatives to find an effective
potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion, Bioorganic
& Medicinal Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.04.034
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Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with
moderately long-lasting suppression of gastric acid secretion
Haruyuki Nishida*, Ikuo Fujimori, Yasuyoshi Arikawa, Keizo Hirase, Koji Ono, Kazuo Nakai,
Nobuhiro Inatomi, Yasunobu Hori, Jun Matsukawa, Yasushi Fujioka, Akio Imanishi, Hideo Fukui,
and Fumio Itoh
Pharmaceutical Research Division: Takeda Pharmaceutical Company, Ltd., 26-1, Muraokahigashi
2-chome, Fujisawa, Kanagawa 251-8555, Japan
*To whom correspondence should be addressed. Phone: +81 466-32-1239. Fax: +81 466-29-4433.
E-mail: haruyuki.nishida@takeda.com
Present address: 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
Keywords: Potassium-competitive acid blocker; transfer behavior to the stomach; rapid onset,
moderately long-lasting acid suppression
Abbreviations: absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox), area
under
the
curve
(AUC),
benzyl
mercaptan
(BnSH),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), hepatic cytochrome P450 2C19
(CYP2C19), hepatic cytochrome P450 3A4 (CYP3A4), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
differential scanning calorimetry (DSC), 2,4-dimethoxybenzyl (DMB), 4-dimethylaminopyridine
(DMAP), dimethyl sulfoxide (DMSO), di-tert-butyl dicarbonate (Boc2O), drug metabolism and
pharmacokinetics (DMPK), electrospray ionization (ESI), half-maximal inhibitory concentration
(IC50), high-performance liquid chromatography (HPLC), high-resolution mass spectrometry
(HRMS), human ether-a-go-go-related gene (hERG), intravenous injection (iv), liquid
chromatography with tandem mass spectrometry (LC/MS/MS), lithium diisopropylamide (LDA),
melting point (mp), methoxy (MeO), N-chlorosuccinimide (NCS), per os (po),
potassium-competitive acid blocker (P-CAB), proton pump inhibitor (PPI), pyridyl (Py), room
temperature (rt), tetrahydrofuran (THF), thermogravimetry-differential thermal analysis (TG-DTA),
thin-layer chromatography (TLC)
Abstract
With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could
perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches
1

based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a
new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the
compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5,
fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring,
showed potent gastric acid-suppressive action and moderate duration of action in animal models. On
the basis of structural properties including a slightly larger Clog P value (1.95), larger log D value
(0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized
compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a
moderate retention time there after single administration. Therefore, compound 20j was selected as a
new promising P-CAB with moderately long duration of action.
1. Introduction
Gastric H+,K+-ATPase is the key enzyme at the final step of gastric acid secretion. Its inhibition is
thought to be especially effective for control of gastric acid secretion; accordingly, the development
of H+,K+-ATPase inhibitors for the treatment of acid-related diseases has attracted considerable
interest.1
Proton pump inhibitors (PPIs) such as lansoprazole, omeprazole, rabeprazole, and pantoprazole
inhibit gastric H+,K+-ATPase by covalently binding to its sulfhydryl group, resulting in inhibition of
gastric acid secretion.2–6 Although PPIs are now the mainstay of therapy for acid-related diseases,
there are several limitations in terms of acid lability, delayed onset of action, variations of efficacy
among patients (largely because of CYP2C19-mediated metabolism), and insufficient inhibition of
nocturnal acid breakthrough.7–11
Potassium-competitive acid blockers (P-CABs), a new class of acid suppressors with a mode of
action different from that of PPIs, are expected to offer some therapeutic benefits such as better
symptom control and faster remission of gastroesophageal reflux disease and of other acid-related
diseases. P-CABs, as the name suggests, inhibit H+,K+-ATPase activity in gastric parietal cells
reversibly and in a potassium-competitive manner.12
In our previous paper,13 we have reported that compound 2a, as a novel P-CAB that has quite low
lipophilicity and excellent ADME-Tox parameters, has a potent H+,K+-ATPase inhibitory activity in
vitro and potent and long-lasting inhibition of histamine-induced gastric acid secretion in rats and
Heidenhain pouch dogs.13 Judging by the finding that compound 2a inhibits histamine-stimulated
gastric acid secretion by approximately 80% in Heidenhain pouch dogs even after 48 h of oral
administration at a dose of 0.8 mg/kg, compound 2a was hypothesized to exert stronger and much
longer inhibition in humans as compared to PPIs. Actually, it holds great promise as a new P-CAB
with unusually long duration of action.
On the other hand, there is a possibility that the duration of action of compound 2a in humans cannot
2

be deduced from the animal data, and we were slightly concerned about a risk of too long duration of
action of compound 2a in humans. Therefore, with the aim to discover a novel excellent P-CAB that
would perfectly overcome the limitations of PPIs, we started to study how to precisely control the
duration of action of pyrrole compounds. Major factors affecting the duration of gastric acid
suppression were found to be H+,K+-ATPase inhibitory activity in vitro and in vivo, the pattern of
distribution to the stomach, and effectiveness of elimination (clearance) from the stomach, but the
contribution rates of such factors were estimated to depend on the overall physicochemical
properties of a compound in question.
Therefore, to understand the duration of gastric-acid-suppressive activity comprehensively, we
decided to evaluate not only basic physicochemical properties such as lipophilicity, basicity, and
membrane penetration, which should determine tissue distribution, but also the actual concentration
in the stomach.
Consequently, gastric and plasma concentration profiles after intravenous administration of
compound 2a were determined by means of cassette dosing experiment, and it turned out that this
compound remains in the stomach at rather high concentrations after 24 h in spite of elimination
from blood plasma. In addition, compound 2a showed significantly more effective transfer to (and
retention in) the stomach as compared to pyrrole lead compound 1 (Table 1).14
Table 1 A series of properties of lead compound 1 and previously optimized P-CAB 2a
Compound Clog P log D pKa
In vitro
H+,K+
In vivo
ATP content hERG
Rat cassette dosinga
Acid
% control
% inhibition
Concentrations (ng/mL or ng/g) and AUC (ng·h/mL or ng·h/g) in rat plasma and stomach
after intravenous administration at a dose of 0.2 mg/kg (as free base)
-ATPase
inhibitory
activities
secretion
in rats
at 100 µM
at 10 µM
(1 mg/kg, iv,
(IC50, nM) % inhibition)
C10min
C1h
C4h
C24h
AUC
plasma stomach plasma stomach plasma stomach plasma stomach plasma stomach
1
3.88
1.45
1.54
0.04
9.48
8.54
30
49
95
98
(22.1)b
100.2
89.1
39.8
17.2
51.5
361.4
602.2
7.3
15
387.7
752.1
2.9
0
244
0
0
0
56
54
3730
2a
628.6
130.5
10277
a All values are averages of three rats.
bATP content at 30 µM (% control)
Because of the above-mentioned concerns, we started searching for a new P-CAB that has low
lipophilicity, excellent ADME-Tox parameters like compound 2a, and moderately long duration of
acid suppression (Figure 1), on the basis of the hypothesis that compound 2a may show a little
excessive duration of action in humans. Consequently, we succeeded in identifying a novel
3

fluoropyrrole derivative by further modifications.
Figure 1. An outline of the search for a new P-CAB with desirable properties.
Herein we report exploration of compounds and identification of a novel fluoropyrrole derivative as
a P-CAB with optimal duration of action.
2. Chemistry
Synthesis of several commercially unavailable 2-pyridyl sulfonylation reagents was accomplished as
shown in Scheme 1. Condensation of commercially available 2-halopyridines 3 with benzyl thiol by
means of a nucleophilic aromatic substitution reaction or a palladium coupling reaction yielded
corresponding 2-benzylthiopyridines 4. 6-MeO derivative 4h was obtained from compound 4b via a
substitution reaction with sodium methoxide. Subsequent oxidation of 4 with N-chlorosuccinimide
(NCS) afforded corresponding sulfonyl halides 5. Reaction products of 4a and 4d were too unstable
to be isolated as sulfonyl chlorides; therefore, they were isolated as stable sulfonyl fluoride
derivatives 5a and 5d after treatment with potassium fluoride.
Scheme 1. Reagents and conditions: (a) BnSH, NaH, THF, rt or 60 °C; (b) BnSH, K2CO3, DMSO,
150 °C; (c) BnSH, Pd2(dba)3, Xantphos, i-Pr2NEt, toluene, 80 °C; (d) NaOMe, MeOH, 60 °C; (e)
4

NCS, AcOH, H2O, then KF, rt; (f) NCS, AcOH, H2O, rt.
Synthesis of several commercially unavailable sulfonylation reagents for 3-pyridyl derivatives was
accomplished as shown in Scheme 2.
Condensation of commercially available or prepared compounds 6 with benzyl mercaptan via a
palladium coupling reaction gave corresponding 7. As for triflate derivative 6a, it was obtained from
compound 6f under basic conditions with a good yield. Subsequent oxidation of compounds 7
afforded compounds 8 in a manner similar to the approach described above.
Scheme 2. Reagents and conditions: (a) N-Phenyl-bis(trifluoromethanesulfonimide), Et3N, THF, rt;
(b) BnSH, Pd2(dba)3, Xantphos, iPr2NEt, toluene, 80 °C; (c) NCS, AcOH, H2O, rt.
Synthesis of fluoropyrrole derivatives 20 was accomplished by starting from commercially available
9, and the synthesis method is shown in Scheme 3.
Initially, the introduction of a fluorine group into the pyrrole ring at position 4 was performed by
directly applying fluorination reactions to several pyrrole intermediates, but these methods were not
practical because the fluorination reaction step poses many difficult problems such as a low yield
and selectivity, the need for precise column chromatography, and the use of an expensive
fluorination reagent. To solve these problems, we attempted to develop an effective method for
synthesis of fluoropyrrole derivatives without direct fluorination of the pyrrole ring. As a result, we
succeeded in the development of a novel method for synthesis of fluoropyrroles, consisting of key
reactions such as a nucleophilic reaction with the carbonyl group of a lactam using pyridyl lithium
and a novel allyl rearrangement reaction (SN2′ reaction) accompanied by desorption of the fluorine
group and double-bond transposition.
As for the synthesis of compound 12, it was successfully achieved by a method similar to the one
described in the literature.15 Condensation of compound 9 with allylamine under neat conditions
gave amide compound 10, which was reacted with Boc2O in the presence of
N,N-dimethyl-4-aminopyridine to obtain Boc-protected compound 11, followed by cyclization to
produce difluorolactam 12.
5

Compound 12 was treated under basic conditions to obtain 13 followed by a nucleophilic addition
reaction with lithiated fluoropyridine to produce 14, which was then subjected to a deprotection
reaction accompanied by dehydration under acidic conditions to obtain 15 with a moderate yield.
Compound 15 was converted to 16 by means of a novel SN2′ reaction, and subsequent sulfonylation
of 16 in the presence of 15-crown-5 under basic conditions yielded 17a. We then used a deprotection
reaction to prepare compound 17b (free base of compound 2a).
Protection of 17b with Boc2O afforded 17c, which was followed by desulfonylation in the presence
of a strong base to obtain key intermediate 18. Compound 18 was then sulfonylated using various
sulfonylation agents 5 and 8 to produce compounds 19, and subsequent treatment with a strong acid
afforded corresponding target compounds 20.
As for compounds 1 and 2a described above and compounds 2b−e to be discussed later, they were
prepared using a procedure similar to a method reported elsewhere.13,14
Scheme 3. Reagents and conditions: (a) allylamine, rt; (b) Boc2O, DMAP, MeCN, rt; (c) CuBr,
6

2,2′-bipyridyl, 1,2-dichloroethane, 80 °C; (d) DBU, THF, 0 °C, then rt; (e) LDA, 2-fluoropyridine,
THF, −78 °C; (f) HCl, AcOH, rt; (g) NaH, DMB, THF, 0 °C; (h) NaH, 15-crown-5,
pyridine-3-sulfonyl chloride, THF, 0 °C; (i) (1) ClCO2CH(Cl)CH3, THF, 0 °C; (2) Et3N, THF, 65 °C;
(3) EtOH, reflux; (4) 1 mol/L NaOH, NaHCO3, H2O, EtOAc, rt; (j) Boc2O, THF, rt; (k) 1 mol/L
NaOH, iPrOH, THF, rt; (l) NaH, 15-crown-5, Ar-sulfonyl chloride or Ar-sulfonyl fluoride, THF, rt;
(m) 4 mol/L HCl/EtOAc, iPrOH or EtOH, EtOAc, rt, or (1) 4 mol/L HCl/EtOAc, iPrOH or EtOH,
EtOAc, rt; (2) NaHCO3, EtOAc; (3) fumaric acid or succinic acid, EtOH or MeOH, EtOAc.
3. Results and discussion
The compounds synthesized were evaluated for their Clog P values, log D values at pH 7.4, and
H+,K+-ATPase-inhibitory activities at pH 6.5 by their IC50 value (in vitro), and many of the
compounds were also analyzed for their inhibitory effects on histamine-induced gastric acid
secretion in anesthetized rats (in vivo), effects on cellular ATP content (cytotoxicity),
hERG-inhibitory activity, and inhibition of CYP3A4 activity. An in vivo assay was conducted by
intravenous administration of the compound at 1 mg/kg, and the total acid output for 3 h after
histamine injection was compared with that after administration of vehicle. The log D values were
measured at pH 7.4 with relative retention time to standard compounds of high-performance liquid
chromatography (HPLC) analysis.16 We also evaluated concentration of the compounds in plasma
and stomach after intravenous administration at a dose of 0.2 mg/kg (as free base) in cassette dosing
experiments on rats. To extrapolate the onset and duration profile of the compounds, drug
concentrations at 10 min and at 1, 4, and 24 h (C10min, C1h, C4h, and C24h) after intravenous
administration were measured in plasma (ng/mL) and stomach (ng/g). In addition, the area under the
curve (AUC) was calculated in plasma (ng·h/mL) and stomach (ng·h/g) as an indicator of stomach
transfer behavior. The results are shown in Tables 1–4.
First, we examined the effects of the fluorine group at position 4 and the effects of the binding site
for heteroaromatics at the first position of the pyrrole ring to assess the possibility of our desired
properties by means of several potent compounds reported in our previous paper.13 The results are
summarized in Table 2.
7

Table 2 Effects of a fluorine group at position 4 (X) and of a binding site for heteroaromatics at the
first position (R1) of the pyrrole ring on activities and various properties of pyrrole compounds
Compound
Clog P log D In vitro
H+,K+
In vivo
ATP content hERG
CYP3A4
Rat cassette dosinga
Acid secretion % control
% inhibition % inhibition Concentrations in rat plasma (ng/mL) and stomach (ng/g) after intravenous
-ATPase
in rats
at 100 µM
at 10 µM
at 10 µM
administration at a dose of 0.2 mg/kg (as free)
inhibitory
(1 mg/kg, iv,
% inhibition)
activities
(IC50, nM)
C10min
C1h
C4h
C24h
AUC
plasma stomach plasma stomach plasma stomach plasma stomach plasma stomach
2a
2b
1.45
0.04
49
210
32
98
96
98
96
81
98
75
95
95
100.2
85.7
64
39.8
4.4
14.4
4.2
51.5
37.1
23.5
20.8
NTb
36.6
26.5
37.4
36
602.2
420
15
8.4
752.1
532.2
613.7
592.4
NTb
0
0
628.6
540.9
639.6
210.3
NTb
0
0
130.5
19.6
41.7
0
54
35
10277
7646
9152
3815
NTb
1.21 –0.85
2.28 –0.83
2.28 –0.69
2c
60
1.4
406.7
522.3
NTb
8.9
0
0
29
2d
32
74.9
78.6
77.5
90.8
100.5
94.8
63
NTb
–9.7
20.5
5.6
8.8
0
0
27
2e
1.21
2.52
1.98
1.98
1.45
0.05
0.54
0.2
120
72
NTb
56.1
28.7
44.5
9
NTb
12.2
6.5
NTb
0
NTb
0
NTb
17.4
0
NTb
42
20a
20b
20c
20d
411.5
592.5
635.4
616.7
954.8
706.3
687.7
809.2
826.7
253.6
193.8
337.1
11717
4566
3865
5757
79
0
0
26
0.45
0.44
60
12.8
7.7
11.5
7.9
0
0
0
41
97
0
0
2.1
33
a All values are averages of three rats.
b Not tested
Unfluorinated 3-pyridyl derivative 2b (AUCstomach = 7646 ng·h/mL) showed significantly lower
AUC in the stomach as compared to fluorinated derivative 2a (AUCstomach = 10227 ng·h/g). In
addition, the maximal concentration time of compound 2b in the stomach after intravenous
administration was 4 h as compared to 1 h for compound 2a. Such a difference in the pattern of
transfer to the stomach was assumed to be mainly based on membrane penetration which is
determined by physicochemical properties including log D (lipophilicity) and pKa (basicity) values.
In our previous paper, it took 150–180 min for pH of a gastric perfusate to reach its maximum value
after intravenous administration of compound 2b in contrast to the rapid onset of pharmacological
action of compound 2a.13 These experimental results on difference in the stomach concentration
between compounds 2b and 2a could explain the difference in the pH behavior of gastric perfusate
during histamine stimulation in anesthetized rats. It is likely that compound 2a (with a fluorine group
introduced at position 4 of the pyrrole ring) caused both rapid transfer and quite long retention in the
stomach because of its suitable balance of moderate log D (0.04) and pKa (8.54) values.
Unfluorinated 3-thienyl derivative 2c (AUCstomach = 9152 ng·h/g) showed a similar pattern of
transfer to the stomach as compared to 2b. Although its AUC in the stomach was a little smaller, the
maximal concentration time in the stomach for 2c after intravenous administration was the same as
8

that of 2b and equaled 4 h. Therefore, the actual onset of pharmacological action of compound 2c
after single administration was also presumed to be not rapid as in 2b. On the other hand,
unfluorinated 2-thienyl derivative 2d (AUCstomach = 3815 ng·h/g) showed much lower AUC in the
stomach as compared to 2c.
These results encouraged us to continue exploration of additional 4-fluorinated compounds that have
a heteroaromatic sulfonyl group at position 1. Although there were no gastric-transfer data regarding
unfluorinated 2-pyridyl derivative 2e, we could assume that the relatively low in vivo activity of
compound 2e (IC50 = 120 nM, 81% inhibition at 1 mg/kg, iv) might be caused by its lower AUC in
the stomach as compared to compound 2b (IC50 = 210 nM, 96% inhibition at 1 mg/kg, iv, AUCstomach
= 7646 ng·h/g). In such a case, the pyrrole derivative was expected to show both rapid transfer to the
stomach and increasing AUC in the stomach after introduction of a fluorine group at position 4.
On the basis of these findings and a hypothesis, we decided to design and explore some additional
4-fluorinated pyrrole derivatives that are expected to show moderate gastric transfer. 4-Fluorinated
2-thienyl derivative 20a (AUCstomach = 11717 ng·h/g) had much higher AUC in the stomach than
unfluorinated 2d did. In addition, the maximal drug concentration time for compound 20a in the
stomach after intravenous administration was 1 h (rapid onset of action might be expected), and the
residual level of compound 20a in the stomach 24 h after intravenous administration was much
lower than that of compound 2a. Unfortunately, compound 20a seemed to be out of the acceptable
range in terms of hERG-inhibitory activity.
4-Fluorinated furyl derivatives 20b (AUCstomach = 4566 ng·h/g) and 20c (AUCstomach = 3865 ng·h/g)
were within a tolerable range in terms of hERG inhibition, but 2-furyl compound 20b did not have
strong in vivo activity. On the other hand, 3-furyl compound 20c showed strong in vivo activity
(95% inhibition at 1 mg/kg, iv). Judging by its gastric transfer properties, it was expected to show
both rapid onset of acid suppression after single administration and moderate duration of action.
4-Fluorinated 2-pyridyl derivative 20d (AUCstomach = 5757 ng·h/g) was found to have enhanced
activities both in vitro and in vivo (IC50 = 97 nM, 95% inhibition at 1 mg/kg, iv) as compared to
those of unfluorinated 2e, as expected. Moreover, compound 20d actually has excellent ADME-Tox
parameters including hERG-inhibitory activity in addition to its good gastric transfer properties,
resembling our desired properties. Therefore, we selected 20d as a lead compound for further
optimization.
Second, we analyzed several analogs of compound 20d in detail to understand the comprehensive
potential of 2-pyridyl derivatives at position 1, and the results are summarized in Table 3.
9

Table 3 Effects of substituent introduction into the 2-pyridyl group at the first position (R1) of the
pyrrole ring on activities and various properties of pyrrole compounds
Compound
Clog P log D In vitro
H+,K+
In vivo
Acid
ATP content hERG
CYP3A4
Rat cassette dosinga
% control
% inhibition % inhibition Concentrations (ng/mL or ng/g) and AUC (ng·h/mL or ng·h/g) in rat plasma and stomach
-ATPase
secretion
at 100 µM
at 10 µM
at 10 µM
after intravenous administration at a dose of 0.2 mg/kg (as free base)
inhibitory in rats
activities
(1 mg/kg, iv,
(IC50, nM) % inhibition)
C10min
C1h
C4h
C24h
AUC
plasma stomach plasma stomach plasma stomach plasma stomach plasma stomach
2a
1.45
1.45
2.21
1.81
1.81
1.95
1.95
1.95
1.62
1.62
0.04
0.44
1.03
0.51
0.64
0.32
0.71
0.48
0.7
49
97
98
95
98
95
95
54
91
92
NT
87
100.2
94.8
69.8
84.5
80
39.8
9
14.4
7.7
51.5
36
602.2
616.7
772.8
617.2
623.5
NTb
15
752.1
809.2
1255
773.4
806.2
NTb
0
0
628.6
337.1
970.8
268.3
426.5
NTb
0
0
130.5
2.1
54
33
10277
5757
14434
4964
6761
NTb
20d
20e
20f
20g
20h
20i
20j
20k
20l
7.9
150
140
280
510
210
73
82.3
38.7
17.6
NTb
13.9
45.1
NTb
NTb
55.8
19
43.5
37.2
54.2
NTb
14.9
10.1
13.1
NTb
0
0
47.9
8.8
50
0
0
38
7.7
0
0
0
52
79.1
83.8
85.5
74
29
NTb
0
NTb
0
NTb
3.3
NTb
41
22.9
4.3
41.7 1083.9 10.3
999.2
926.6
NTb
527
8550
10378
NTb
39.4
NTb
25
946.9
NTb
8.1
NTb
5
0
681.7
NTb
0
28.9
NTb
0
35
240
100
46
NTb
0
NTb
0
NTb
22
0.42
86.5
21.7
369.3
525.7
346.7
5179
a All values are averages of three rats.
b Not tested
Although compound 20d remained in the stomach for 24 h after intravenous administration, its
residual concentration seemed to be quite small in terms of our drug concept implying long-lasting
acid suppression for 24 h. The introduction of a methoxy (MeO) group into the 2-pyridyl (Py)
moiety of 20d maintained strong in vivo activity in spite of weaker in vitro activity. 6-MeO-2-Py
derivative 20e (AUCstomach = 14434 ng·h/g) showed better gastric transfer than 20d did. Nonetheless,
an unacceptable hERG-inhibitory activity was observed, unfortunately.
4-MeO-2-Py derivative 20f (AUCstomach = 4964 ng·h/g) showed better gastric transfer properties
regarding its residual level in the stomach after 24 h, accompanied by acceptable hERG inhibition,
and moreover, it appeared to have moderate duration of acid suppression.
On the other hand, 5-MeO-2-Py derivative 20g (AUCstomach = 6761 ng·h/g) was not detected in the
stomach after 24 h in spite of a slight increase in AUC in the stomach. Compound 20g was presumed
to have faster clearance from the stomach than 20d did. As for the introduction of a methyl group
into the 2-pyridyl moiety of 20d, 3-Me-2-Py derivative 20h did not show strong activities either in
vitro or in vivo, but both 6-Me-2-Py derivative 20i (AUCstomach = 8550 ng·h/g) and 4-Me-2-Py
10

derivative 20j (AUCstomach = 10378 ng·h/g) exerted relatively good activities accompanied by
acceptable ADME-Tox parameters and a moderate stomach concentration.
Unfortunately, in the case of the introduction of a fluorine group into the 2-pyridyl moiety of 20d,
6-F-2-Py derivative 20k strongly inhibited CYP3A4, and 5-F-2-Py derivative 20l did not show good
in vivo activity in spite of its in vitro activity similar to that of 20d.
Finally, we evaluated several analogs of compound 2a to elucidate the effects of substituents in the
3-pyridyl group at position 1 on such properties as lipophilicity and basicity (Table 4).
Table 4 Effects of substituent introduction into the 3-pyridyl group at position 1 (R1) of the pyrrole
ring on activities and various properties of pyrrole compounds
Compound
Clog P log D In vitro
H+,K+
In vivo
ATP content hERG
CYP3A4
Rat cassette dosinga
Acid secretion % control
% inhibition % inhibition Concentrations (ng/mL or ng/g) and AUC (ng·h/mL or ng·h/g) in rat plasma and stomach
-ATPase
in rats
at 100 µM
at 10 µM
at 10 µM
after intravenous administration at a dose of 0.2 mg/kg (as free base)
inhibitory (1 mg/kg, iv,
activities
% inhibition)
(IC50, nM)
C10min
C1h
C4h
C24h
AUC
plasma stomach plasma stomach plasma stomach plasma stomach plasma stomach
2a
20m
20n
20o
20p
20q
20r
1.45
2.19
2.19
1.62
1.95
1.95
1.95
1.95
0.04
0.75
1.44
0.83
0.48
0.43
0.61
0.62
49
98
NTb
NTb
99
100.2
86.9
66.9
88.9
97.4
90.9
86.9
76.7
39.8
NTb
NTb
22.7
14.8
28.2
NTb
24.8
14.4
53.1
45.9
27
51.5
28
602.2
539
15
10.1
NTb
8.3
752.1
722.1
NTb
0
0
628.6
427.4
NTb
0
0
130.5
0
54
33
10277
6568
NTb
390
160
200
210
120
140
180
NTb
43
NTb
NTb
0
NTb
0
NTb
38.3
0
NTb
38
330.4
507
605.5
577
425.2
299.7
250.7
NTb
6599
4806
4248
NTb
92
30.1
40
25.3
50.1
NTb
40.1
8
0.3
0
0
32
98
359.6
NTb
8.4
618.5
NTb
0
0
41
87
49.7
–1.2
NTb
10.8
NTb
0
NTb
0
NTb
219.1
NTb
41
20s
97
671.5
1124
1182.8
18284
a All values are averages of three rats.
b Not tested
The introduction of a substituent into the 3-pyridyl moiety of compound 2a reduced in vitro
activities in any cases of chlorination, fluorination, or methylation. In addition, both 2-Cl-3-Py
derivative 20m and 5-Cl-3-Py derivative 20n inhibited CYP3A4 activity beyond our acceptable level.
In contrast, 5-F-3-Py derivative 20o (AUCstomach = 6559 ng·h/g) showed promising gastric transfer
behavior and acceptable toxicity parameters accompanied by strong in vivo activity. 2-Me-3-Py
derivative 20p (AUCstomach = 4806 ng·h/g) and 4-Me-3-Py derivative 20q (AUCstomach = 4248
ng·h/g) both had good ADME-Tox parameters, but we assumed that the duration of acid suppression
was probably too short from the standpoint of their gastric transfer in rats. Although 5-Me-3-Py
11

derivative 20r did not exert enough in vivo activity in addition to unacceptable CYP3A4 inhibition,
6-Me-3-Py derivative 20s (AUCstomach = 18284 ng·h/g) showed strong in vivo acid suppression
accompanied by acceptable toxicity parameters. Nevertheless, its AUC in the stomach was much
larger than that of compound 2a in rats, and its residual level in the stomach at 24 h after
administration was also obviously too high.
To clarify the actual pH profile in the stomach, we evaluated the effects of compounds 20c, 20d, 20e,
20f, 20g, 20i, 20j, 20o, and 20s on the pH of a gastric perfusate under conditions of histamine
stimulation in anesthetized rats (Figure 2).
12

Figure 2. Effects of intravenous administration of compounds 2a (A)13, 20c (B), 20d (C), 20e (D),
20f (E), 20g (F), 20i (G), 20j (H), 20o (I), and 20s (J) on the pH of gastric perfusate under conditions
of histamine stimulation in anesthetized rats. Each data point represents mean SE from three to six
rats.
The pH value of saline under these experimental conditions was 6.0 to 6.3. Intravenous infusion of
histamine 2HCl at 8 mg/kg/h stimulated gastric acid secretion and decreased pH of the gastric
perfusate to ~2.
In our previous study, intravenous administration of compound 2a at a dose of 0.7 mg/kg caused a
relatively rapid increase in pH of the gastric perfusate to ~6, and the effect was sustained for more
than 5 h after administration (Figure 2A).13 In contrast, intravenous administration of selected
compounds clearly changed the pH profile of the gastric perfusate of compound 2a at a dose of 1
mg/kg except for compound 20s.
Compounds 20c, 20f, 20g, and 20i caused a rapid elevation of perfusate pH after intravenous
administration at 1 mg/kg, but the perfusate pH did not reach 5 obviously in any case (Figure 2B, E,
F, and G). On the other hand, intravenous administration of 20d, 20e, 20j, 20o, or 20s at a dose of 1
mg/kg increased pH of the gastric perfusate to ~5 or greater.
Compound 20d caused rapid elevation of perfusate pH to approximately 5 after the administration of
20d at 1 mg/kg, whereas perfusate pH rapidly decreased thereafter (Figure 2C). Compound 20d
seemed to clearly have short duration of acid suppression in line with our assumption from gastric
transfer properties such as AUC in the stomach and the residual level after 24 h. Compound 20e
unfortunately possessed unacceptable parameters in terms of CYP3A4 and hERG inhibition (Table
3), but had a strong pH-increasing effect and, moreover, showed a certain level of sustained action
accompanied by significantly shorter duration of action relative to compound 2a (Figure 2D).
Compound 20j, which possessed acceptable ADME-Tox parameters, rapidly increased pH of the
gastric perfusate to approximately 6, and the effect moderately diminished thereafter (Figure 2H).
Although compound 20o showed declining behavior similar to that of 20j, the elevation of perfusate
pH by 20o exceeded only 5, and furthermore, the onset of acid suppression was not so rapid. Its
characteristic pH behavior may also be due to some extent to the gastric concentration after
intravenous administration and the AUC in the stomach (Table 4).
As for compound 20s, rapid onset of pharmacological action, and rather long-lasting acid
suppression were observed as in compound 2a. Judging by the gastric transfer properties of this
compound (Table 4), further long-lasting acid suppression may be assumed. According to these
results, compound 20j, which showed moderate duration of action in rats, was selected for further
analysis. We studied the effects of oral administration of compound 20j in rats and dogs (Figures 3
and 4). As shown in Figure 3, compound 20j inhibited histamine-stimulated gastric acid secretion in
13

anesthetized rats in a dose-dependent manner.
Figure 3. Effects of oral administration of compound 20j on histamine-stimulated gastric acid
secretion in anesthetized rats. Each column represents mean SE from seven or eight rats. Statistical
significance of the difference was determined by the one-tailed Shirley-Williams test; *p < 0.025
compared to vehicle.
Compound 20j also completely inhibited histamine-stimulated gastric acid secretion in Heidenhain
pouch dogs after oral administration at a dose of 1 mg/kg (Figure 4A). Its duration of action was
much longer than that of lansoprazole at 3 mg/kg, po (Figure 4B13), but significantly shorter than
that of compound 2a (Figure 4C13). Moreover, its effect was obviously longer as compared to that of
unmethylated compound 20d at 1 mg/kg, po (Figure 4D), and its distinct acid suppression was
observed even 24 h after the administration.
14

Figure 4. Effects of oral administration of compound 20j (A), lansoprazole (B),13 compound 2a
(C),13 and compound 20d (D) on histamine-stimulated gastric acid secretion in Heidenhain pouch
dogs. Each data point represents mean SE from three or four dogs.
Compound 20j was designed to have weak lipophilic properties (Clog P = 1.95) and moderate
basicity; the log D value was 0.48 at pH 7.4 and pKa (acid dissociation constant) of the side chain
amino group portion was 8.73. On the basis of these physicochemical properties such as the log D
value (0.48 at pH 7.4) increased by the 5-Me-2-Py group and similar pKa (8.73) after the
introduction of fluorine as compared to compound 2a, compound 20j was presumed to have rapid
onset and moderate duration of action after single administration because of rapid transfer into the
acidic secretory canaliculi in the stomach and remaining there over an appropriate period (Figure 5).
15

Compound Clog P log D
(pH 7.4)
pKa
In vitro
H+,K+
In vivo
Acid
Rat cassette dosinga
Concentrations (ng/mL or ng/g) and AUC (ng·h/mL or ng·h/g) in rat plasma and stomach after
intravenous administration at a dose of 0.2 mg/kg (as free base)
-ATPase secretion
inhibitory in rats
activities (1 mg/kg, iv,
(IC50, nM) % inhibition)
C10min
C1h
C4h
C24h
AUC
plasma stomach plasma stomach plasma stomach plasma stomach plasma stomach
1
3.88
1.45
1.45
1.95
1.54
0.04
0.44
0.48
9.48
30
49
97
73
95
98
95
92
17.2
51.5
36
361.4
602.2
616.7
946.9
7.3
15
387.7
752.1
809.2
926.6
2.9
0
244
0
0
0
0
0
56
54
33
35
3730
10277
5757
2a
8.54
NTb
8.73
628.6
337.1
681.7
130.5
2.1
20d
20j
7.9
8.1
0
39.4
0
28.9
10378
a All values are averages of three rats.
b Not tested
Figure 5. Identification of a novel potent P-CAB called 20j, which has moderately long duration of
acid suppression
These results indicate that the pharmacological effect of compound 20j is superior to that of
lansoprazole. This new compound also showed good acid resistance and limited susceptibility to
CYP polymorphism (data not shown) unlike lansoprazole. Furthermore, the overall DMPK and
safety profiles of 20j were excellent as in compound 2a.
Additionally, compound 20j was expected to have equal or slightly shorter duration of action in
humans as compared with TAK-438,17–21 which was recently launched in Japan for the treatment of
gastric ulcer, duodenal ulcer, erosive esophagitis, prevention of low-dose aspirin- or non-steroidal
anti-inflammatory drug-induced ulcer recurrence, and as an adjunctive therapy for Helicobacter
pylori eradication, judging by 20j’s pharmacological effects in rats and Heidenhain pouch dogs.
On the basis of these findings, compound 20j, which has physicochemical properties different from
those of TAK-438 (e.g., in terms of lipophilicity and basicity), could be a promising alternative as a
P-CAB, if the need arises.
4. Conclusion
We synthesized novel pyrrole derivatives that show moderate duration of acid suppression—in
16

accordance with our hypothesis based on previously optimized compound 2a—and we evaluated
their potency including stomach transfer and safety profiles. Our initial plan for identification of a
desired compound with moderate duration of action involved studying both the effects of a fluorine
group at position 4 and of hetero-aromatic groups at position 1 of the pyrrole ring regarding the
stomach concentration behavior. Consequently, we found that the pyrrole compound that has both a
fluorine group at position 4 and a 2-pyridyl sulfonyl group at position 1 possesses potentially
favorable properties. Eventually, our experiments revealed that the combination of 2-F-3-Py group at
position 5, a fluorine group at position 4, and 4-Me-2-Py sulfonyl group at the first position of the
pyrrole ring was probably the most suitable for both potent activity and moderately long duration of
action accompanied by low lipophilicity and acceptable ADME-Tox parameters.
Thus, identified compound 20j showed potent H+,K+-ATPase inhibitory activity in vitro and potent
moderately long-lasting inhibitory effects on histamine-stimulated gastric acid secretion in rats and
Heidenhain pouch dogs. We succeeded in identifying a new P-CAB with moderately long duration
of action as a possible alternative to TAK-438 if the need arises.
5. Experimental section
Experimental procedures and characterization data for all synthetic intermediates are reported in
Supplementary data.
5.1. General
The pKa values were measured by pH-metric assays using a Sirius T3 system (Sirius Analytical Ltd.,
UK). The assay measures the concentration of H+ ions in solution between pH 2 and 12 using a pH
electrode (Ag/AgCl). Melting points were determined on a Yanagimoto micro melting point
apparatus or Büche B-545 or by differential scanning calorimetry (DSC) or TG-DTA analyses. DSC
analyses were conducted using a DSC1 system (Mettler Toledo, Switzerland). The thermograms
were obtained at a temperature of 25–300 °C and a heating rate of 5 °C/min under nitrogen gas at a
flow rate of 40 mL/min. The powders (~1 mg) were weighed in an aluminum pan, crimped, and then
placed in the thermal analysis chamber. TG-DTA analyses were carried out by Sumika Chemical
Analysis Service, Ltd. Nuclear magnetic resonance (1H-NMR) spectra were recorded on a Varian
Gemini-200, Varian Mercury-300, and Bruker AV-300M spectrometer. Chemical shifts are given in δ
values (ppm) using tetramethylsilane as the internal standard. Coupling constants are reported in
hertz (Hz). Spectral splitting patterns are designated as follows: s, singlet; br, broad; d, doublet; t,
triplet; q, quartet; m, multiplet. High-resolution mass spectrometry (HRMS) experiments were
carried out by Sumika Chemical Analysis Service, Ltd. All MS experiments were conducted using
electrospray ionization (ESI) in positive or negative ion mode. Elemental analyses were obtained
from Takeda Analytical Laboratories, Ltd., or Sumika Chemical Analysis Service, Ltd. Thin-layer
17

chromatography (TLC) analyses were carried out on Merck Kieselgel 60 F254 plates or Fuji Silysia
Chemical, Ltd. Chromatorex NH-TLC plates. Silica gel column chromatography was run using
Merck 0.063-0.200 mm silica gel 60, Fuji Silysia Chemical, Ltd. 100-200 mesh Chromatorex NH
silica DM1020 or Purif-Pack (SI 60 µM or NH 60 µM, Fuji Silysia Chemical, Ltd.). Commercial
reagents and solvents were used without additional purification.
5.2.
1-[4-Fluoro-5-(2-fluoropyridin-3-yl)-1-(thiophen-2-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanami
ne hydrochloride (20a)
To a solution of compound 19a (276 mg, 0.59 mmol) in EtOAc (2 mL) and iPrOH (1 mL) was added
4 mol/L HCl/EtOAc (5 mL), and the mixture was stirred at room temperature for 2 h. The reaction
mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH to
obtain compound 20a as colorless crystals (168 mg, 70%): mp 196 °C; 1H-NMR (DMSO-d6) δ 2.56
(3H, s), 4.05 (2H, s), 7.22 (1H, dd, J = 5.1 Hz, 4.0 Hz), 7.48–7.56 (2H, m), 7.85 (1H, d, J = 5.5 Hz),
7.93 (1H, ddd, J = 9.5 Hz, 7.5 Hz, 2.0 Hz), 8.18 (1H, dd, J = 4.9 Hz, 1.3 Hz), 8.40 (1H, dq, J = 4.9
Hz, 0.9 Hz), 9.12 (2H, brs); Anal. Calcd for C15H14ClF2N3O2S2: C, 44.39; H, 3.48; N, 10.35. Found:
C, 44.31; H, 3.41; N, 10.35.
5.3.
1-[4-Fluoro-5-(2-fluoropyridin-3-yl)-1-(furan-2-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine
hydrochloride (20b)
Compound 20b was prepared from 19b following a similar procedure as for the preparation of
compound 20a from 19a. Colorless crystals (77%): mp 229 °C; 1H-NMR (DMSO-d6) δ 2.58 (3H, s),
4.07 (2H, s), 6.77 (1H, dd, J = 3.8 Hz, 1.7 Hz), 7.17 (1H, d, J = 3.8 Hz), 7.50 (1H, ddd, J = 7.1 Hz,
5.2 Hz, 1.4 Hz), 7.80 (1H, d, J = 5.5 Hz), 7.94 (1H, ddd, J = 9.3 Hz, 7.5 Hz, 1.6 Hz), 8.13 (1H, s),
8.40 (1H, d, J = 4.3 Hz), 9.04 (2H, brs); Anal. Calcd for C15H14ClF2N3O3S: C, 46.22; H, 3.62; N,
10.78. Found: C, 46.08; H, 3.50; N, 10.65.
5.4.
1-[4-Fluoro-5-(2-fluoropyridin-3-yl)-1-(furan-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine
hydrochloride (20c)
Compound 20c was prepared from 19c following a similar procedure as for the preparation of
compound 20a from 19a. Colorless crystals (76%): mp 234 °C; 1H-NMR (DMSO-d6) δ 2.57 (3H, s),
4.05 (2H, s), 6.72 (1H, dd, J = 1.9 Hz, 0.8 Hz), 7.49 (1H , ddd, J = 7.3 Hz, 5.0 Hz, 1.7 Hz), 7.85 (1H,
d, J = 5.7 Hz), 7.91 (1H, ddd, J = 9.6 Hz, 7.5 Hz, 1.9 Hz), 7.96 (1H, t, J = 1.9 Hz), 8.33 (1H, dd, J =
1.5 Hz, 0.8 Hz), 8.36–8.41 (1H, m), 9.32 (2H, brs); Anal. Calcd for C15H14ClF2N3O3S: C, 46.22; H,
18

3.62; N, 10.78. Found: C, 46.26; H, 3.58; N, 10.80.
5.5.
1-[4-Fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine
hydrochloride (20d)
To a solution of compound 19d (221 mg, 0.477 mmol) in EtOAc (2 mL) and EtOH (2 mL) was
added 4 mol/L HCl/EtOAc (4 mL), and the mixture was stirred at room temperature for 2 h. The
reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from
EtOH/EtOAc (1/3) to obtain compound 20d as colorless crystals (175 mg, 92%): mp 187–188 °C;
1H-NMR (DMSO-d6) δ 2.56 (3H, s), 4.06 (2H, s), 7.42–7.48 (1H, m), 7.72–7.92 (4H, m), 8.07–8.15
(1H, m), 8.33–8.38 (1H, m), 8.70–8.74 (1H, m), 9.18 (2H, brs); Anal. Calcd for C16H15ClF2N4O2S: C,
47.94; H, 3.77; N, 13.98. Found: C, 48.01; H, 3.74; N, 14.04.
5.6.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methyl
methanamine hydrochloride (20e)
Compound 20e was prepared from 19e following a similar procedure as for the preparation of
1
compound 20a from 19a. Colorless crystals (51%): mp 202–204 °C; H-NMR (DMSO-d6) δ 2.58
(3H, s), 3.79 (3H, s), 4.08 (2H, s), 7.21 (1H, d, J = 8.4 Hz), 7.32 (1H, d, J = 6.9 Hz), 7.42–7.46 (1H,
m), 7.81–7.89 (2H, m), 7.94 (1H, dd, J = 8.4 Hz, 6.9 Hz), 8.33–8.35 (1H, m), 8.96 (2H, brs); Anal.
Calcd for C17H17ClF2N4O3S: C, 47.39; H, 3.98; N, 13.00. Found: C, 47.27; H, 3.90; N, 13.00.
5.7.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methyl
methanamine hydrochloride (20f)
Compound 20f was prepared from 19f following a similar procedure as for the preparation of
1
compound 20a from 19a. Colorless crystals (79%): mp 205–208 °C; H-NMR (DMSO-d6) δ 2.57
(3H, s), 3.87 (3H, s), 4.06 (2H, s), 7.17 (1H, d, J = 2.3 Hz), 7.33 (1H, dd, J = 5.7 Hz, 2.7 Hz), 7.46
(1H, ddd, J = 6.9 Hz, 5.2 Hz, 1.5 Hz), 7.80 (1H, d, J = 5.7 Hz), 7.89 (1H, ddd, J = 9.3 Hz, 7.6 Hz,
1.7 Hz), 8.30–8.39 (1H, m), 8.51 (1H, d, J = 5.7 Hz), 9.01 (2H, brs); Anal. Calcd for
C17H17ClF2N4O3S: C, 47.39; H, 3.98; N, 13.00. Found: C, 47.47; H, 3.97; N, 12.97.
5.8.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methyl
methanamine hydrochloride (20g)
Compound 20g was prepared from 19g following a similar procedure as for the preparation of
19

1
compound 20a from 19a. Colorless crystals (88%): mp 229–233 °C; H-NMR (DMSO-d6) δ 2.54
(3H, s), 3.91 (3H, s), 4.03 (2H, s), 7.38–7.46 (1H, m), 7.51–7.58 (1H, m), 7.62–7.70 (1H, m),
7.75–7.87 (2H, m), 8.33 (1H, dt, J = 4.7 Hz, 0.8 Hz), 8.36 (1H, d, J = 3.0 Hz), 9.20 (2H, brs); Anal.
Calcd for C17H17ClF2N4O3S: C, 47.39; H, 3.98; N, 13.00. Found: C, 47.35; H, 4.27; N, 12.77.
5.9.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylm
ethanamine fumarate (20h)
To a solution of compound 19h (107 mg, 0.223 mmol) in EtOAc (2 mL) and iPrOH (1 mL) was
added 4 mol/L HCl/EtOAc (3 mL), and the mixture was stirred at room temperature for 1 h, and then
concentrated under reduced pressure. A solution of NaHCO3 was added to the residue, and the
mixture was extracted with EtOAc. The extract was washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The residue was purified by basic silica gel column
chromatography (n-hexane/EtOAc = 4/1–1/1), and then the obtained oil (45 mg) was dissolved in
EtOAc (2 mL). A solution of fumaric acid (13.6 mg, 0.117 mmol) in EtOH (2 mL) was added at
room temperature, and the mixture was concentrated under reduced pressure. The residue was
crystalized from EtOH/EtOAc (1/10) to produce compound 20h as colorless crystals (51 mg, 46%):
1
mp 150 °C; H-NMR (DMSO-d6) δ 2.35 (3H, s), 2.38 (3H, s), 3.73 (2H, s), 6.53 (2H, s), 7.32–7.39
(1H, m), 7.48 (1H, d, J = 5.7 Hz), 7.63 (1H, dd, J = 7.8 Hz, 4.4 Hz), 7.74–7.83 (1H, m), 7.93 (1H, d,
J = 7.6 Hz), 8.27 (1H, d, J = 4.2 Hz), 8.41 (1H, d, J = 4.5 Hz), 3H not detected. Anal. Calcd for
C21H20F2N4O6S: C, 51.01; H, 4.08; N, 11.33. Found: C, 50.70; H, 4.16; N, 11.19.
5.10.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylm
ethanamine hydrochloride (20i)
Compound 20i was prepared from 19i following a similar procedure as for the preparation of
1
compound 20a from 19a. Colorless crystals (53%): mp 217–220 °C; H-NMR (DMSO-d6) δ 2.49
(3H, s), 2.54 (3H, s), 4.04 (2H, s), 7.43–7.48 (1H, m), 7.58–7.64 (2H, m), 7.79 (1H, d, J = 5.4 Hz),
7.88–7.99 (2H, m), 8.34–8.35 (1H, m), 9.21 (2H, brs); Anal. Calcd for C17H17ClF2N4O2S: C, 49.22;
H, 4.13; N, 13.51. Found: C, 49.23; H, 4.11; N, 13.49.
5.11.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylm
ethanamine succinate (20j)
To a solution of compound 19j (333 mg, 0.696 mmol) in EtOAc (2 mL) and iPrOH (1 mL) was
added 4 mol/L HCl/EtOAc (3 mL), and the mixture was stirred at room temperature for 1 h, and then
20

concentrated under reduced pressure. The residue was crystalized from EtOAc, and the obtained
crystals were recrystallized from EtOAc/EtOH (5/1) to produce
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylm
ethanamine hydrochloride (191 mg, 66 % from 19j) as colorless crystals; mp 181–185 °C; 1H-NMR
(DMSO-d6) δ 2.37 (3H, s), 2.56 (3H, s), 4.05 (2H, s), 7.45 (1H, ddd, J = 7.3 Hz, 5.0 Hz, 1.7 Hz),
7.54 (1H, s), 7.59–7.66 (1H, m), 7.77–7.90 (2H, m), 8.33–8.40 (1H, m), 8.55 (1H, d, J = 4.9 Hz),
9.11 (2H, brs); Anal. Calcd for C17H17ClF2N4O2S: C, 49.22; H, 4.13; N, 13.51. Found: C, 49.30; H,
4.42; N, 13.61.
A solution of NaHCO3 was added to the crystals (751 mg, 1.81 mmol), and the mixture was
extracted with EtOAc. The extract was washed with brine, dried over anhydrous MgSO4, filtered and
concentrated
in
vacuo
to
afford
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylm
ethanamine (647 mg, 62% from 19j) as a yellow oil: 1H-NMR (CDCl3) δ 2.38 (3H, s), 2.45 (3H, s),
3.64 (2H, s), 7.23–7.30 (2H, m), 7.33 (1H, d, J = 5.7 Hz), 7.36 (1H, s), 7.88 (1H, ddd, J = 9.3 Hz,
7.4 Hz, 1.9 Hz), 8.22–8.29 (1H, m), 8.45 (1H, d, J = 4.5 Hz), 1H not detected.
The obtained oil (189 mg, 0.50 mmol) was dissolved in EtOAc (2 mL). A solution of succinic acid
(59 mg, 0.50 mmol) in EtOH (2 mL) was added at room temperature, and the mixture was
concentrated under reduced pressure. The resulting solid was recrystallized from EtOH/H2O (10/1)
1
to obtain compound 20j as colorless crystals (232 mg, 58% from 19j): mp 166–168 °C; H-NMR
(DMSO-d6) δ 2.34 (3H, s), 2.36 (4H, s), 2.37 (3H, s), 3.66 (2H, s), 7.39–7.49 (2H, m), 7.52 (1H, s),
7.55–7.63 (1H, m), 7.86 (1H, ddd, J = 9.5 Hz, 7.4 Hz, 1.9 Hz), 8.34 (1H, ddd, J = 4.9 Hz, 1.9 Hz, 0.9
Hz), 8.54 (1H, d, J = 4.9 Hz), 3H not detected. Anal. Calcd for C21H22F2N4O6S: C, 50.80; H, 4.47; N,
11.28. Found: C, 50.77; H, 4.52; N, 11.37.
5.12.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylme
thanamine hydrochloride (20k)
Compound 20k was prepared from 19k following a similar procedure as for the preparation of
1
compound 20d from 19d. Colorless crystals (53%): mp 215–218 °C; H-NMR (DMSO-d6) δ 2.58
(3H, s), 4.08 (2H, s), 7.44–7.48 (1H, m), 7.65–7.78 (3H, m), 7.87–7.92 (1H, m), 8.28–8.37 (2H, m),
8.85 (2H, brs); Anal. Calcd for C16H14ClF3N4O2S: C, 45.88; H, 3.37; N, 13.38. Found: C, 45.51; H,
3.38; N, 13.26.
5.13.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylme
thanamine hydrochloride (20l)
21

Compound 20l was prepared from 19l following a similar procedure as for the preparation of
1
compound 20a from 19a. Colorless crystals (51%): mp 200–204 °C; H-NMR (DMSO-d6) δ 2.58
(3H, s), 4.07 (2H, s), 7.41–7.49 (1H, m), 7.80 (1H, d, J = 5.5 Hz), 7.82–7.91 (2H, m), 8.05 (1H, dt, J
= 8.6 Hz, 2.8 Hz), 8.36 (1H, ddd, J = 4.9 Hz, 1.9 Hz, 0.9 Hz), 8.78 (1H, d, J = 2.8 Hz), 8.97 (2H,
brs); Anal. Calcd for C16H14ClF3N4O2S: C, 45.88; H, 3.37; N, 13.38. Found: C, 45.95; H, 3.46; N,
13.43.
5.14.
1-{1-[(2-Chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylme
thanamine hydrochloride (20m)
Compound 20m was prepared from 19m following a similar procedure as for the preparation of
compound 20d from 19d. Colorless crystals (90%): mp 219 °C; 1H-NMR (DMSO-d6) δ 2.59 (3H, s),
4.09 (2H, s), 7.40–7.48 (1H, m), 7.52 (1H, dd, J = 8.0 Hz, 4.5 Hz), 7.72–7.79 (1H, m), 7.81–7.91
(1H, m), 7.93–8.02 (1H, m), 8.32–8.36 (1H, m), 8.75 (1H, dd, J = 4.7 Hz, 1.7 Hz), 9.21 (2H, brs).
Anal. Calcd for C16H14Cl2F2N4O2S: C, 44.15; H, 3.24; N, 12.87. Found: C, 43.98; H, 3.41; N, 12.86.
5.15.
1-{1-[(5-Chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}-N-methylme
thanamine hydrochloride (20n)
Compound 20n was prepared from 19n following a similar procedure as for the preparation of
1
compound 20a from 19a. Colorless crystals (95%): mp 211–216 °C; H-NMR (DMSO-d6) δ 2.57
(3H, s), 4.05 (2H, s), 7.52 (1H, ddd, J = 7.3 Hz, 5.1 Hz, 1.9 Hz), 7.93 (1H, ddd, J = 9.6 Hz, 7.5 Hz,
2.0 Hz), 8.01 (1H, d, J = 5.5 Hz), 8.11 (1H, t, J = 2.2 Hz), 8.43 (1H, ddd, J = 4.9 Hz, 1.8 Hz, 0.8 Hz),
8.57 (1H, d, J = 2.1 Hz), 9.05 (1H, d, J = 2.1 Hz), 9.33 (2H, brs); Anal. Calcd for C16H14Cl2F2N4O2S:
C, 44.15; H, 3.24; N, 12.87. Found: C, 44.20; H, 3.56; N, 12.90.
5.16.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylme
thanamine hydrochloride (20o)
Compound 20o was prepared from 19o following a similar procedure as for the preparation of
1
compound 20a from 19a. Colorless crystals (65%): mp 228–233 °C; H-NMR (DMSO-d6) δ 2.57
(3H, s), 4.05 (2H, s), 7.51 (1H, ddd, J = 7.4 Hz, 5.1 Hz, 1.9 Hz), 7.92 (1H, ddd, J = 9.5 Hz, 7.6 Hz,
1.9 Hz), 8.01 (1H, d, J = 5.3 Hz), 8.05 (1H, dt, J = 7.7 Hz, 2.4 Hz), 8.36–8.46 (1H, m), 8.49 (1H, s),
9.03 (1H, d, J = 2.7 Hz), 9.36 (2H, brs); Anal. Calcd for C16H14ClF3N4O2S: C, 45.88; H, 3.37; N,
13.38. Found: C, 45.94; H, 3.35; N, 13.47.
22

5.17.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylm
ethanamine fumarate (20p)
Compound 20p was prepared from 19p following a similar procedure as for the preparation of
1
compound 20h from 19h. Colorless crystals (85%): mp 182–185 °C; H-NMR (DMSO-d6) δ 2.41
(3H, s), 2.49 (3H, s), 3.77 (2H, s), 6.53 (2H, s), 7.31 (1H, dd, J = 8.1 Hz, 4.7 Hz), 7.42 (1H, ddd, J =
7.2 Hz, 5.1 Hz, 1.7 Hz), 7.47 (1H, dd, J = 8.3 Hz, 1.5 Hz), 7.71 (1H, d, J = 5.7 Hz), 7.84 (1H, ddd, J
= 9.6 Hz, 7.5 Hz, 1.9 Hz), 8.28–8.34 (1H, m), 8.73 (1H, dd, J = 4.7 Hz, 1.7 Hz), 3H not detected;
Anal. Calcd for C21H20F2N4O6S: C, 51.01; H, 4.08; N, 11.33. Found: C, 51.06; H, 4.10; N, 11.37.
5.18.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylm
ethanamine fumarate (20q)
Compound 20q was prepared from 19q following a similar procedure as for the preparation of
1
compound 20h from 19h. Colorless crystals (78%): mp 205–208 °C; H-NMR (DMSO-d6) δ 2.33
(3H, s), 2.40 (3H, s), 3.76 (2H, s), 6.53 (2H, s), 7.43 (1H, ddd, J = 7.3 Hz, 5.1 Hz, 1.8 Hz), 7.52 (1H,
d, J = 5.1 Hz), 7.72 (1H, d, J = 5.7 Hz), 7.85 (1H, ddd, J = 9.5 Hz, 7.4 Hz, 1.9 Hz), 8.14 (1H, s), 8.32
(1H, ddd, J = 4.9 Hz, 1.9 Hz, 0.9 Hz), 8.70 (1H, d, J = 5.1 Hz), 3H not detected; Anal. Calcd for
C21H20F2N4O6S: C, 51.01; H, 4.08; N, 11.33. Found: C, 50.95; H, 4.11; N, 11.37.
5.19.
1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylm
ethanamine fumarate (20r)
Compound 20r was prepared from 19r following a similar procedure as for the preparation of
1
compound 20h from 19h. Colorless crystals (76%): mp 178–182 °C; H-NMR (DMSO-d6) δ 2.33
(3H, s), 2.35 (3H, s), 3.70 (2H, s), 6.54 (2H, s), 7.50 (1H, ddd, J = 7.3 Hz, 5.1 Hz, 1.9 Hz),
7.63–7.71 (2H, m), 7.90 (1H, ddd, J = 9.6 Hz, 7.5 Hz, 2.0 Hz), 8.36–8.41 (1H, m), 8.42 (1H, d, J =
2.3 Hz), 8.76 (1H, d, J = 1.3 Hz), 3H not detected; Anal. Calcd for C21H20F2N4O6S: C, 51.01; H,
4.08; N, 11.33. Found: C, 50.88; H, 4.06; N, 11.31.
5.20.
Bis{1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(6-methypyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylm
ethanamine}fumarate (20s)
Compound 20s was prepared from 19s following a similar procedure as for the preparation of
1
compound 20h from 19h. Colorless crystals (70%): mp 192–195 °C; H-NMR (DMSO-d6) δ 2.30
(3H, s), 2.56 (3H, s), 3.61 (2H, s), 6.51 (1H, s), 7.45–7.53 (2H, m), 7.60 (1H, d, J = 5.7 Hz), 7.79
23

(1H, dd, J = 8.3 Hz, 2.3 Hz), 7.91 (1H, ddd, J = 9.6 Hz, 7.5 Hz, 1.9 Hz), 8.35–8.40 (1H, m), 8.48
(1H, d, J = 2.3 Hz), 2H not detected; Anal. Calcd for C19H18F2N4O4S: C, 52.29; H, 4.16; N, 12.84.
Found: C, 52.32; H, 4.28; N, 12.86.
5.21. Measurement of H+,K+-ATPase activity
Measurement of H+,K+-ATPase activity was done using the method described elsewhere.14
5.22. An assay of inhibition of acid secretion in anesthetized rats by intravenous administration
This assay was performed using the method described elsewhere.14
5.23. An assay of inhibition of acid secretion in anesthetized rats by oral administration
This assay was conducted in a manner similar to a method reported elsewhere.13 A test compound at
doses of 1, 2, 3, or 4 mg/kg (as the free base) or vehicle was administered orally 1 h before pylorus
ligation and histamine 2HCl (30 mg/kg, subcutaneous) administration. Gastric contents were
collected 3 h after histamine administration, and the total acid output was calculated.
5.24. Measurement of pH of a gastric perfusate under conditions of histamine stimulation in
anesthetized rats
This assay was performed by the method described elsewhere.13
5.25. An assay of inhibition of acid secretion in Heidenhain pouch dogs
This assay was performed by the method described elsewhere.13
5.26. A pharmacokinetic experiment in rats
Test compounds were administered intravenously via cassette dosing to fasted male Sprague-Dawley
rats. After that, blood and the stomach were collected. The blood samples were centrifuged to obtain
the plasma fraction. The plasma and a 20% stomach homogenate in saline were deproteinized with
acetonitrile containing an internal standard. After centrifugation, the supernatant was diluted and
centrifuged again. The compound concentrations in the supernatant were measured by LC/MS/MS.
5.27. A cytotoxicity assay
This assay was carried out by the method described elsewhere.13
5.28. Whole-cell patch-clamp for a hERG inhibition assay
This assay was conducted using a procedure described elsewhere.13
24

5.29. Measurement of CYP3A4-inhibitory activity
This activity of test compounds was evaluated by incubating 100 µmol/L testosterone with 10
nmol/L CYP3A4 derived from CYP3A4-expressing insect cells (BD Bioscience) in the presence of
10 µmol/L test compound. The reaction mixture was incubated for 15 min at 37 °C. The
concentration of 6β-hydroxytestosterone was measured by means of an HPLC system equipped with
an ultraviolet light detector.
Acknowledgments
We thank Dr. Toshihiro Imaeda for helpful discussions, and Drs. Takashi Ichikawa and Toshimasa
Tanaka for proofreading this manuscript.
A. Supplementary data
Supplementary data associated with this article can be found, in the online version.
Funding
This research received no specific grant from any funding agency in the public, commercial, or
not-for-profit sectors.
Disclosure
The authors declare that they have no conflicts of interest.
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27

Graphical Abstract
Exploration of pyrrole derivatives to find an
effective potassium-competitive acid blocker
with moderately long-lasting suppression of
gastric acid secretion
Haruyuki Nishida, Ikuo Fujimori, Yasuyoshi Arikawa, Keizo Hirase, Koji Ono, Kazuo Nakai, Nobuhiro
Inatomi, Yasunobu Hori, Jun Matsukawa, Yasushi Fujioka, Akio Imanishi, Hideo Fukui, and Fumio Itoh
Pharmaceutical Research Division: Takeda Pharmaceutical Company, Ltd., 26-1, Muraokahigashi 2-chome,
Fujisawa, Kanagawa 251-8555, Japan
28