Evaluation of basic, heterocyclic ring systems as templates for use as potassium competitive acid blockers (pCABs)

Article abstract of DOI:10.1016/j.bmcl.2009.07.002

A variety of basic, heterocyclic templates has been reported as potassium-competitive, acid pump antagonists. Herein, we report a comparison of potencies of these templates and others to establish which offers the best start point for further systematic o

Full text of DOI:10.1016/j.bmcl.2009.07.002

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6813–6817
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Evaluation of basic, heterocyclic ring systems as templates for use
as potassium competitive acid blockers (pCABs)
*
Terry Panchal , Nick Bailey, Mark Bamford, Emmanuel Demont, Richard Elliott, Irene Farre-Gutierrez,
Neil Garton, Thomas Hayhow, Gail Hutley, Antoinette Naylor
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of basic, heterocyclic templates has been reported as potassium-competitive, acid pump antag-
onists. Herein, we report a comparison of potencies of these templates and others to establish which
offers the best start point for further systematic optimisation. Modifications were carried out to improve
the developability profile of the more potent 1H-pyrrolo[2,3-c]pyridine template, affording molecules
with improved overall in vitro characteristics versus the reported clinical candidate AR-H047108, and
comparable to the clinically efficacious AZD-0865.
Received 15 May 2009
Revised 1 July 2009
Accepted 1 July 2009
Available online 4 July 2009
Keywords:
Potassium competitive acid blockers
APA
Ó 2009 Elsevier Ltd. All rights reserved.
Acid secretion
Acid pump antagonists
1H-Pyrrolo[2,3-c]pyridine
Potassium-competitive acid blockers (pCABs), also known as
acid pump antagonists (APAs), have become a focus of attention
as a means of achieving rapid but potentially long-lasting inhibi-
tion of gastric acid secretion. Unlike the irreversible proton pump
inhibitors (PPIs) they do not require acid activation and would be
expected to be significantly more stable than PPIs under all phys-
iological conditions. Thus, their pharmacokinetic half life can be
significantly longer allowing active drug species to be present
whenever parietal cells become activated. Therefore, full acid sup-
pression from first dose together with long duration of action are
expected to be key features of these reversible inhibitors. Further-
more, the potential use of mildly basic molecules as pCABs may
lead to accumulation in the acidic parietal cell, leading to similar
concentrations to those delivered by PPIs, affording additional
opportunities for selectivity, potency and duration of action.1
A number of basic heterocyclic molecules (e.g., 1–5; Fig 1) have
been reported as pCABs and some progressed to clinical trials. In-
deed AZD-0865 (3) has been reported to show the desired rapid
onset and long duration of acid suppression in GERD patients with
excellent effect on clinical outcome comparable to that of the PPI
esomeprazole.2 The relative in vitro profiles of these pCABs has
not previously been reported, however our own comparison sug-
gests their in vitro developability profiles may not always be opti-
mal, for example, CS526 (1) and AR-H047108 (2) show significant
CyP450 interaction (Table 1). In this Letter, we describe work to
evaluate related compounds having different heterocyclic cores
to gain a deeper understanding of which template(s) may offer
the best start-points for potential optimisation. We then describe
optimisation of the physico-chemical properties of one of the more
potent templates, the 1H-pyrrolo[2,3-c]pyridines, to achieve po-
tent compounds with at least comparable in vitro profiles to those
of previously reported clinical candidate pCABs, (1–4).
To aid the selection of templates for further optimisation, an
evaluation of heterocyclic biaryl ring systems was carried out hav-
ing a range of pKa’s and bearing key functionality identified from
previously reported work.16–19
Previously reported SAR in the imidazo[1,2-a]pyridine series6
indicates the 2,6-dialkyl benzylamino substituent to give enhanced
potency. This has been rationalised by modelling20 of analogues of
analogues of SCH28080 and the conformationally restricted tricy-
clic analogue Soraprazan (4) (reported H+/K+ ATPase pIC50 7.0)10
which suggests the preferred orientation of the pendant phenyl
ring is orthogonal to the core imidazopyridine ring.
Reported SAR17,19,21 also indicates that the 2,3-dimethyl substi-
tution in the imidazo[1,2-a]pyridine template (e.g., 5) also gives
enhanced potency (1000Â relative to the 2,3-unsubstituted ana-
logue). The benzylamine at the 8-position of this compound (H+/
K+ ATPase pIC50 9.1) is more potent than the corresponding 8-ben-
zyloxy analogue22 (6, H+/K+ ATPase pIC50 7.6). To allow direct com-
parison of potencies, 2,3-dimethyl substitution of the core
template (generalised nomenclature) and 8-(2,6-dimethyl benzyl)
amino substituents were used as standard groups on the range of
alternative templates evaluated.
* Corresponding author.
E-mail address: Terry.A.Panchal@gsk.com (T. Panchal).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.002

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T. Panchal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6813–6817
OMe
O
O
CN
HO
N
N
N
N
N
N
H2N
N
H
N
O
N
N
N
N
(s)
(s)
O
NH
NH
O
NH
HO
F
(1) CS 526 3-5
(2) AR-H0471086,7
(AstraZeneca)
(3) AZD-0865 8,9
(AstraZeneca)
(4) Soraprazan10,11
(Nycomed)
(5) SCH2808012-14
(Schering-Plough)
(Sankyo-Novartis)
Figure 1. Examples of basic heterocyclic pCABs.3–14
Table 1
GSK data on reported pCABs
H+/K+ATPase
pIC50
Parietal cells:15
pIC50
CYP450 IC50
3A4(7BQ)
(l
M) 1A2, 2C9, 2C19, 2D6, 3A4a(DEF),
Time dependent inhibitionb,c (TDI) 3A4,
2D6 IC50
CLi (ml/min/kg.) Rat, Dog,
Hu.
,
(1) 6.8
6.55
7.63
7.25
7.78
1.2, 0.8, 5.1, 4.4, 6.0, 14
4.3, 3.6, >20, 9.2, 3.8, 3.9
>50, 31, >100, 58, 9, 12
2.0, 54, >100, >100, 82, 9, 12
1.2 (DEF), 0.6
0.4 (DEF), —
3.9 (DEF)/10 (7BQ), 1.0
1.7 (DEF), —
30, 38, 16
14, 3, 6.5
4, 0.9, 1.3
8.5, —, 8.0
(2) 7.0
(3) 6.5
(5) 7.4
a
3A4 DEF assay uses diethoxyfluorescein as CYP 3A4 substrate. The 3A4 7BQ assay uses 7-benzyloxyquinoline.
IC50 fold change from t = 0 to 10 min when pre-incubation of 10 min before IC50 determination.
A twofold increase in IC50 (TDI >2) is considered as a positive result, TDI at CYP 1A2, 2C9 and 3A4 7BQ were not measured in this project.
b
c
Of the various templates evaluated (Table 2), only the 1H-pyr-
profiles can be improved by appropriate substitution. We also ex-
pected reduction in lipophilicity to improve overall developability
characteristics including P450 inhibition and intrinsic clearance
(CLi), and reduction in basicity to improve CyP450 2D6 profile in
particular.30
Having established 1H-pyrrolo[2,3-c]pyridine (18) as the only
one from those evaluated having comparable potency to the
imidazo[1,2-a]pyridine template (5), further SAR evaluation of
(18) was carried out. The effect of methyl substituents in the
2,3-positions on the heterocyclic ring and the influence of the
2,6-dimethyl groups on the benzyl substituent were first
examined to establish if the SAR in the 1H-pyrrolo[2,3-c]pyridine
series matched that of the imidazo[1,2-a]pyridine series
(Table 3).
rolo[2,3-c]pyridine (18)23 gave, in our hands, comparable potency
to the imidazo[1,2-a]pyridine (5), however the pyrrolo[1,2-a]pyra-
zine (8) and the imidazo [1,2-a]pyrazine24 (9) also have potency
levels that may be of interest for further optimisation. Though
the inhibitory activity of the imidazo[1,2-a]pyridine is reported
to reside in the positively charged protonated form,25 hence a
smaller percentage of the less basic compounds is protonated un-
der the conditions of the H+/K+ATPase inhibition (pH 7.4) it appears
that basicity per se is not sufficient for activity (e.g., 14 is only
weakly active) (Table 2).
We were unable to derive a correlation of H+/K+ATPase inhibi-
tion (measured at pH 7.4) with pKa. This was further complicated
by the finding that a number of analogues were poorly soluble
making pKa measurement difficult. Also, we obtained poor predic-
tions for pKa of these systems using calculated methods.27 As the
position of the most basic centre in the 1H-pyrrolo[2,3-c]pyridine
(18) is expected to be at the pseudo aminopyridyl centre, it sug-
gests that the precise position of the basic centre relative to the
pendant aryl ring may not be critical for potency (e.g., 5 vs 18),
but a basic nitrogen at generic positions 1 or 7 (see figure Table
2 for numbering system) appears optimal for good activity. Intro-
duction of an additional nitrogen atom in position 5 (e.g., 11, 12,
14) appears to be less tolerated and nitrogen at position 1 gives
higher potency than at position 3 when having a basic nitrogen
at position 7 (cf. 17 vs 18).
Replacement of the methyl substituent (R2) with hydrogen to
give (21) gave only a minor decrease in potency compared to the
2,3-dimethyl analogue (18) whereas removal of both methyl
groups at C2,C3 (22) reduced potency more substantially, suggest-
ing C3 methyl is the key substituent for potency. Removal of the
2,6-dimethyl groups on the benzyl substituent (23) gave approxi-
mately 10-fold reduction in potency (relative to 18), presumably
because the orthogonal conformation of the benzyl substituent is
no longer as preferred.31
Our strategy to improve the developability profile of the 1H-
pyrrolo[2,3-c]pyridine (18) initially focused on substitution at
the C5 position with suitable heteroaromatic and heterocyclyl
groups to modulate overall properties, a strategy which we have
also shown to be successful in the imidazo[1,2-a]pyridine tem-
plate.21 Although C5 substitution reduced the potency relative
to the unsubstituted analogue (18), an effect also observed with
the corresponding substitution in the imidazo[1,2-a]pyridine ser-
ies,21 we were encouraged to find that H+/K+ ATPase-inhibitory
potencies, comparable to that of (3) were still obtained for some
analogues, with significant inhibition of histamine-induced parie-
tal cell acid secretion (Table 4). Moreover, reducing basicity (see
An attempt to derive a CoMFA model28,29 in order to further ex-
plain this data was unsuccessful as all statistical measures indi-
cated no relationship between activity and CoMFA electrostatic
or steric fields.
Evaluation of the in vitro DMPK profiles (Table 2) of the most
active analogues (H+/K+ ATPase pIC50 >6.8) indicated that these
minimally substituted analogues all had poor P450 profiles and,
or high intrinsic clearance. However, the in vitro DMPK profile of
AZD-0865 (3) versus unsubstituted compound (5) suggests these

T. Panchal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6813–6817
6815
Table 2
H+/K+ATPase potency and invitro DMPK profiles for range of templates evaluated
O
5
3
4
HO
N
2
N
N
N
H
N
6
N
N
N
1
N
7
NH
8
7
5
3
8
N
N
N
N
N
N
N
N
N
N
N
H
N
10
11
12
3,5,7-20
9
N
N
N
N
N
N
N
N
N
N
N
N
16
13
O
14
15
6
N
N
N
N
S
N
N
N
H
18
S
N
20
19
17
Ex
H+/K+ATPase pIC50
Parietal cell pIC50
7.25
pKa
CHI Log D26
pH 7.4
CYP450 IC50
3A4(DEF), 3A4(7BQ)
(
l
M) 1A2, 2C9, 2C19, 2D6,
CLi (ml/min/kg.)
Rat, Dog, Hu
3
5
6
7
8
6.5
9.1
7.6
4.1
7.6
7.1
4.0
6.1
5.9
5.5
4.8
5.3
4.5
6.8
9.4
<4
6.27
7.28
7.41
6.03
7.92
2.14
4.20
3.38
50, 31, >100, 58, 9, 12
3.9, 3.9, 1.9, 2.7, 5.5, 9.6
0.7, 16, 6.2, 2.3, 5.5, 18
4, 0.9, 1.3
50, 28, 7.6
6.85
6.55
IA@1 lM
3.54
3.40
3.50
3.53
2.53
6.1, 14, 4.7, <0.1, 4.7, 1.6
50, —, 11
9
10
11
12
13
14
15
16
17
18
19
20
7.2
7.35
>100, >100, >10, 0.3, 8.8, >100
2.1, 8.8, 9.2, 35, 13, 9
9.0, —, 2.8
47, —, 8.0
36%@50
7.13
l
M
M
7.42
7.49
5.81
9.14
3.28
2.09
2.27
2.04
2.29
31, 68, 27, <0.1, 12, 21
14, 6.5, 3.4
22%@50
7.15
l
41,66, 6.9, <0.1, 3.1, 4.3
14, 33, 1.8, <0.1, 9.0, 9.6
28, 17, 3.8
50, 19, 5
<4
Table 3
Further SAR for substitution of 1H-pyrrolo[2,3-c]pyridine series
R1
4
3
5
R2
2
6 N
N
1
7
NH
H
R3
R3
Ex
R1
R2
R3
pKa
H+/K+ATPase pIC50
Parietal cell15 % inhib. @50 nM
18
21
22
23
Me
Me
H
Me
H
H
Me
Me
Me
H
nd
9.4
9.0
6.8
8.4
67.3
92.5
nd
8.71
8.63
8.79
Me
Me
98.5
24, 27, 28) significantly improved the CYP450 2D6 inhibition
profile as expected and gave only minor reductions in cell po-
tency albeit a more significant decrease in H+/K+ ATPase-inhibi-
tory potencies were observed. We were also pleased to find
that intrinsic clearance was also reduced by substitution at C5
(compared to 18), for example, 24, 25, and 27.
Achieving potency as well as developability properties within
an appropriate range in the pyrrolo[2,3-c]pyridine template,

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T. Panchal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6813–6817
Table 4
Profiles of 5 substituted 1H-pyrrolo[2,3-c]pyridines
Het
N
N
H
NH
Het
H+/K+ATPase pIC50
9.4
pKa
CHI Log D pH 7.4
Parietal cell
assay pIC50
CYP450 IC50
2C19, 2D6, 3A4(DEF), 3A4(7BQ)
(
l
M) 1A2, 2C9,
CLi (ml/min/kg.)
Rat, Hu
18 H
nd
2.30
7.1
14, 33, 1.8, <0.1, 9.0, 9.6
50, 19, 5
24
O
7.4
6.3
7.4
4.71
3.18
5.31
3.77
nd
29, 3.3, 20, >33, 3, 90
3.7, 6.7, 0.3, 0.6, 7.7, 6.6
26, 1.4, 6.4, 1.9, 1.0, 1.8
2.9, 2.7
N
25 Ph
Insuff. Sol.a
6.32
6.5
6.8
3.9, <0.5
nd
26
O
N
27
O
Insuff. Sol.a
Insuff. Sol.a
2.83
4.12
6.7
6.5
35, 61, 66, 25, 22, 22
4.3, 1.6
nd
O
5.9
5.1
N
28
>100, 2.3, 62,60, 1.3, 2.2
O
N
29
H
N
O
6.5
nd
2.54
6.8
22, 2.7, 8.2, 0.7, 1.6, 1.6
6.0, 1.3
N
a
Examples 25, 27, 28 were insufficiently soluble for pKa’s to be determined.
merely by modification at C5 alone proved elusive; we therefore
investigated further modification. A useful synthetic handle in
this regard is the N1-position. (Table 5). N1 ethyl substitution
on the C5 pyridone to give (30), maintained potency. Although
N1 allyl (33) is potent versus H+/K+ ATPase, it is poorly active
in the cell assay. In both examples, intrinsic clearance is in-
creased and overall CyP450 profile is poorer relative to the
unsubstituted N1 analogue (27), possibly due to an increase in
lipophilicity. We found that substitution with the more hydro-
philic 2-hydroxyethyl group (e.g., 31, 32) was tolerated and gave
Table 5
Profiles of 1,5 disubstituted 1H-pyrrolo[2, 3-c]pyridines
Het
N
N
R
NH
Het
R
H+/K+ATPase pIC50
pKa
CHI Log D
pH 7.4
Parietal cell
assay pIC50
CYP450 IC50
2C19, 2D6, 3A4(DEF), 3A4(7BQ)
(
l
M) 1A2, 2C9,
CLi (ml/min/kg.)
Rat, Hu
30
O
O
Et
7.4
4.0
3.9
6.7
65, 0.7, 6.5, 18, 2.9, —
41, 22
21.9,12.1
6.5,6.9
20,13
N
N
31
32
(CH2)2OH
(CH2)2OH
CH2CH@CH2
6.8
6.6
7.5
4.5
5.4
4.0
3.12
2.93
4.06
6.6
>100, 11.4, 40, 45.5, 5.6, —
>100, 13, >100, 36, 6.0, 11
62,0.5,6.0,26,2.4,—
O
O
7.1
N
33
O
I.A@300 nM
N

T. Panchal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6813–6817
6817
Br
Cl
Br
Br
c
b
a
N
N
H
N
N
N
N
H
NO2
NO2
NH
Cl
Br
Br
O
O
N
N
N
e
d
N
N
N
H
NH
NH
OH
Scheme 1. Preparation of 1,5-disubstituted 1H-pyrrolo[2,3-c]pyridine (31). Reagents and conditions: (a) Br2, AcOH, 50 °C, (88%); (b) 3-bromo2-butene, Mg/THF, 0 °C (22%) (c)
2,6-dimethylbenzylamine, potassium carbonate 190 °C, (80%); (d) 2-pyridone, copper iodide, cesium carbonate, 1,2-dimethylethylamine, NMP, (31%). (e) (i) sodium hydride,
(ii) 2-[(2-bromoethyl)oxy]tetrahydro-2H-pyran, DMF, (iii) tosic acid, methanol (44%).
9. Lilljequist, L., Lindkvist, M., Nordberg, P., Pettersson, U. and Sebhatu, T. PCT Int.
improved CyP450 profiles. Compound 32 was of particular inter-
Appl. WO200558895, 2005.; (a) Abelo, A.; Andersson, M.; Holmberg, A. A.;
Karlsson, M. O. Eur. J. Pharm. Sci. 2006, 29, 91; (b) Andersson,K. SCI mtg,
London.
est as it showed a good balance of in vitro PK characteristics,
with H+/K+ATPase and cell potency and an overall in vitro profile
10. Simon, W. A. J. Pharm. Exp. Ther. 2007, 321, 866.
11. Postius, S; Simon, W-A; Grundler, G; Hanauer, G; Huber, R; Kromer, W; Sturm,
comparable to that of previously reported clinical candidates
such as (2) and (3).
E; Senn-Bilfinger, J. PCT Int. Appl. WO 2000017200, 2000.
The synthesis of (31) is representative of the approach taken
for the preparation of this class of compound and is outlined in
Scheme 1. Thus the commercially available 2,6-dichloro-3-nitro-
pyridine was converted to the corresponding dibromide which
was followed by Bartoli azaindole formation.32 Reaction with
2,6-dibromobenzylamine gave selective displacement of the C7
bromide. Displacement of the C5 bromide with pyridinone using
Ullman conditions,33 followed by N1 alkylation with 2-[(2-
bromoethyl)oxy]tetrahydro-2H-pyran then removal of the THP
protecting group to yield the desired compound (31).
12. Kaminski, J. J.; Bristol, J. A.; Puchalski, C.; Lovey, R. G.; Elliott, A. J.; Guzik, H.;
Solomon, D. M.; Conn, D. J.; Domalski, M. S.; Wong, S.-C.; Gold, E. H.;
Long, J. F.; Chiu, P. J. S.; Steinberg, M.; McPhail, A. T. J. Med. Chem. 1985,
28, 876.
13. Kaminski, J. J.; Hilbert, J. M.; Pramanik, B. N.; Solomon, D. M.; Conn, D. J.; Rizvi,
R. K.; Elliott, A. J.; Guzik, H.; Lovey, R. G.; Domalski, M. S.; Wong, S.-C.;
Puchalski, C.; Gold, E. H.; Long, J. F.; Chiu, P. J. S.; McPhail, A. T. J. Med. Chem.
1987, 30, 2031.
14. Kaminski, J. J.; Puchalski, C.; Solomon, D. M.; Rizvi, R. K.; Conn, D. J.; Elliott, A. J.;
Lovey, R. G.; Guzik, H.; Chiu, P. J. S.; Long, J. F.; McPhail, A. T. J. Med. Chem. 1989,
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In conclusion, evaluation of potency and in vitro DMPK profiles
of a range of bicyclic templates has shed light on SAR and key
requirements for potency. Although no clear correlations between
the range of 5,6 ring system templates and potencies could be de-
rived, SAR suggests weak basicity is required for activity and that a
heteroatom basic centre is best tolerated at positions 1 and 7 (gen-
eralised nomenclature).
The imidazo[1,2-a]pyridine template (5) and the 1H-pyrrol-
o[2,3-c]pyridine (18) were identified as being the most potent tem-
plates and we have demonstrated that the in vitro DMPK profile of
the parent 1H-pyrrolo[2,3-c]pyridine (18) can be improved by suit-
able substitution at C5 and N1 in order to modify pKa and lipophil-
icity. In particular the 1H-pyrrolo[2,3-c]pyridine compound (32)
has been identified as having a similar overall in vitro profile to
that of the reported clinical candidate imidazo[1,2-a]pyridine,
AZD-0865 (3). Further profiling and modifications of compound
(32) will be reported in a later publication.
16. Beil, W.; Hackbarth, I.; Sewing, K. F. Brit. J. Pharm. 1986, 88, 19.
17. Kaminski, J. J.; Bristol, J. A.; Puchalski, C.; Lovey, R. G.; Elliott, A. J.; Guzik, H.;
Solomon, D. M.; Conn, D. J.; Domalski, M. S. J. Med Chem. 1985, 28, 876.
18. Bristol, J A.; Lovey, R G. Imidazo[1,2-b]pyridazines. U.S. US 4464372, 1984.
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20. (a) Kaminski, J. J.; Puchalski, C.; Solomon, D. M.; Rizvi, R. K.; Conn, D. J.; Elliott,
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21. Bailey, N.; Bamford, M. J.; Brissey, D.; Brookfield, J.; Demont, E.; Elliott, R.;
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26. CHI is a measure of lipophilicity by fast gradient HPLC. CHI log D is different
from octanol/water log D, it is more similar to a water/hexane partition, as it is
sensitive to H-bond donor groups. CHI is derived directly from a gradient
reversed phase chromatographic retention time.
References and notes
27. ACD labs v8. This predicts Àlog (acid–base ionisation constant(s)) for the
molecule at 25 °C and zero ionic strength. Parameters on which this calculation
is based are drawn from over 23,000 experimental values of literature
compounds under different temperatures and ionic strengths in aqueous
solution.
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