Orally active C-6 heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine acid pump antagonists (APAs)

Article abstract of DOI:10.1016/j.bmcl.2009.04.127

Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imi

Full text of DOI:10.1016/j.bmcl.2009.04.127

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3602–3606
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Orally active C-6 heteroaryl- and heterocyclyl-substituted
imidazo[1,2-a]pyridine acid pump antagonists (APAs)
*
Nick Bailey, Mark J. Bamford, Delphine Brissy, Joanna Brookfield, Emmanuel Demont , Richard Elliott,
Neil Garton, Irene Farre-Gutierrez, Thomas Hayhow, Gail Hutley, Antoinette Naylor, Terry A. Panchal,
Hui-Xian Seow, David Spalding, Andrew K. Takle
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:
Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at
low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class
of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in ani-
mal models of gastric acid secretion following oral administration, as well as a good overall developabil-
ity profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6
position and optimization of developability characteristics through modulation of global physico-chem-
ical properties.
Received 2 April 2009
Revised 24 April 2009
Accepted 25 April 2009
Available online 3 May 2009
Keywords:
Acid pump antagonist
Potassium competitive acid blocker
Imidazo[1,2-a]pyridine
Ó 2009 Elsevier Ltd. All rights reserved.
Acid pump antagonists (APAs, also known as potassium-com-
petitive acid blockers or P-CABs) are reversible inhibitors of the
H+/K+ ATPase responsible for the acidification of the stomach. They
are expected to have similar efficacy but faster onset in the treat-
ment of gastric acid-related disorders compared with the current
gold standard proton pump inhibitors (PPIs), which bind irrevers-
ibly to the same enzyme.1
functionality.6 As described herein, we subsequently expanded
the SAR elsewhere in the template to fine-tune the overall
properties.
Tetra-substituted imidazo[1,2-a]pyridines of structure 4 can be
readily obtained (Scheme 1) from commercially available 2-amino
pyridines. Reductive amination (X = NH2) led to key intermediates
5. Regioselective substitution of the C-8 substituent (4, X = Br) with
p-methoxybenzyl alcohol gave phenol 6 after deprotection. This
was alkylated to give intermediate 7. In the case of C-linked C-8
substituents, the Suzuki coupling using arylethenyl boronic acid
was carried out prior to hydrogenation and C-6 bromination to give
8 followed by reaction with an alpha-bromo ketone to give the C-8
carbon linked intermediate 9. Intermediates 5, 7 or 9 were further
functionalized at the C-6 position using Ullman or Buchwald chem-
Imidazo[1,2-a]pyridine derivatives such as AR-HO47108 1 or
AZD-0865 2 (Fig. 1) attracted our attention since they are reported
to have shown efficacy in animal models of gastric acid secretion
and in the clinic at low oral doses.2 Although recent reports indi-
cate toxicity issues have been reported for 1,3 a detailed SAR and
broader evaluation of analogues in this C6-substituted imi-
dazo[1,2-a]pyridine series has not previously been reported.
Our own in vitro exploration of these compounds showed that
the amide functionality at C-6 in 1 and 2 leads to a drop in enzyme
potency compared to the parent compound 3. However, the
in vitro clearance and CYP450 inhibition profiles were improved
(Table 1). We hypothesized that these improvements were primar-
ily due to a reduced lipophilicity (CHI log D) or to reduced electron
density at key regions of the molecule (as evidenced by reduced
pKa of 1 (6.2) versus 3 (7.0)—this may also partly explain the
reduced enzyme potency).5 We therefore decided to explore other
means of modulating these features by C-6 modification. Our
investigations quickly focused on C6-heteroaryl and heterocyclic
O
O
H2N
N
HN
OH
N
N
N
N
N
NH
NH
NH
3
1
2
* Corresponding author. Tel.: +44 0 1438 764319; fax: +44 0 1438 764799.
E-mail address: emmanuel.h.demont@gsk.com (E. Demont).
Figure 1. Examples of imidazo[1,2-a]pyridine APAs.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.127

N. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3602–3606
3603
Table 1
In vitro profile of reference APAs and C6-modified imidazo[1,2-a]pyridines
R6 =
R6
H
O
O
O
N
O
N
O
N
N
N
N
HN
N
12
14
15
13
NH
H
N
N
N
O
N
N
N
19
16
17
18
Compd H+/K+ ATPase pIC50 Parietal cell %Ia Rat H+ secretion %Ib Rat [Bl]b
(
l
M) Cli (r,d,h) ml/min/g liverc CYP IC50
(l
M)4 1A2, 2C9, 2C19, CHI log D @ pH 7.4d
2D6, 3A4 (DEF, 7BQ)
*
1
2
3
7.0
6.5
8.2
8.4
8.3
8.1
7.9
7.4
7.6
6.5
6.9
107
ꢀ100
94
94
98
0.14
0.62
14, 3.0, 6.5
4, 0.9, 1.3
4.3, 3.6, 20, 9.2, 3.8, 3.9
>100, 14, >100, 46, 8.4, 14
1.5, 1.5, 0.5, 1.1, 4.7, 6.3
26, 3.4, 17, 39, 1.7, 2.6
>100, 14, 34, 41, 6.8, 22
35, 0.86, 9.3, 11, 2.9, 2.1
100, 17, >50, 97, 13, 48
>100, 0.63, 5.2, 1.7, 1.3, 1.8
13, 2.5, 16, 17, 17, 6.7
2.52
2.14
4.32
1.8
2.79
3.60
2.67
4.11
3.07
4.63
2.62
*
82 ( 45)
0.015
0.019
0.072
0.604
0.125
0.355
0.716
0.490
0.041
>50, —, 12
38, 0.9, 2.9
19, <0.5, 2.9
8.2, 4.0, 2.9
6.0, 1.0, 1.9
13, 2, 3.3
6.9, 2.7, 2.0
6.2, 1.9, 1.7
45, 4.8, 4.9
12
13
14
15
16
17
18
19
1
2
85
94
113
104
93
*
93 ( 84)
22
28
*
117
11
92 ( 83)
24
1.3, 3.2, 13, 2.2, 1.8, 1.5
>100, 5.8, >100, >100, 6.5, 5.3
1e
40f
a
% Inhibition of pentagastrin stimulated accumulation of 14C-aminopyrine by 50 nM compound.
As for Tables 4–6, 70 min following 3 mg/kg dose (or * 1 mg/kg) in pentagastrin stimulated acid secretion in rat. See Ref. 8 for procedure. Concentration of compound in rat
b
blood ([Bl]) was determined in parallel.
c
Intrinsic clearance in rat (r), dog (d) and human (h) liver microsomes.
Chromatographic hydrophobicity index, measured at pH 7.4. pKa were in general not determined as a result of poor solubility—calculated log D and pKa using eg the ACD
d
software generally resulted in poor predictions in this series of analogues.
e
107% at 150 nM.
92% I @ 10 mg/kg p.o. Nd = not determined.
f
istry to give the desired APAs.7 Alternatively, amine C-8 substitu-
ent could be introduced via Buchwald coupling after introduction
of the C-6 substituent (4?10?11).
A range of heteroaryl/heterocyclyl substituents at C-6 gave
acceptable H+/K+ ATPase inhibition (see representative examples
Table 1) and some even gave improved inhibition compared with
O
R3
R3
Br
R2
NH2
Br
6
Br
Br
N
N
R3
N
R2
R2
N
N
c, d
8
a
X
X
OH
b
X = NH2, Br
4
6
e
R3
R3
Br
B(OH)2
Br
Br
N
N
R2
N
N
R
R2
N
NH2
N
NH2
f-h
Br
H2C
N
X
Br
CH2
R
R
R'
R
7 X = O
9 X = CH2
8
5
R3
R3
Ar
i
N
N
R2
R2
N
N
Br
4 (X = Br)
X
10 X = Br
11 X = NRR'
j
Scheme 1. Access to C-6 heteroaryl/heterocyclyl imidazo[1,2-a]pyridines. Reagents and conditions: (a) NMP, 180 °C, microwave or EtOH, reflux; (b) R–X, X = Cl or Br, Na2CO3,
KI, DMF; (c) PMB-OH, NaH, DMF, 0–90 °C; (d) CH2Cl2, CF3COOH, 25 °C; (e) NaH, DMF, 25 °C then R–X, X = Cl, Br; (f) Pd(PPh3)4, K2CO3, dioxan, reflux; (g) Pd/C, H2 (1 atm),
MeOH, 25 °C; (h) Br2, CH2Cl2, 25 °C; (i) Ar-H, CuI, Cs2CO3, trans 1,2-diaminocyclohexane, DMF, 120 °C or ArH, Pd2(dba)3, Xantphos, Cs2CO3, dioxane, reflux; (j) NHRR0,
Pd2(dba)3, dicyclohexylphosphino-20-(N,N-dimethylamino)biphenyl, tBuONa, dioxane, 120 °C, microwave irradiation.

3604
N. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3602–3606
Table 2
SAR at C-6 from leads 15 and 17
HO
O
N
N
R6 =
N
N
N
N
N
R6
HO
N
N
21
23
22
N
N
N
N
O
NH
O
N
NH
N
N
NH2
N
24
O
O
N
N
20
25
26
CYP IC50
Compd
H+/K+ ATPase pIC50
Parietal cell pIC50
Rat H+ secretion %Ia
Cli (r,h,d) ml/min/g liver
(l
M) 2C9, 3A4 (DEF, 7BQ)
CHI log D @ pH 7.4
15
17
20
21
22
23
24
25
26
7.9
7.6
7.0
7.6
7.5
7.1
7.8
7.0
6.7
7.3
7.2
7.1
7.0
6.8
6.5
7.3
93
92
88
95
93
8
92
Nd
0
6.0, 1.0, 1.9
6.9, 2.7, 2.0
31, 1.7, 6.7
5.4, 1.3, 1.6
4.6, <0.4, 1.3
4.9, 0.7, 1.7
9.6, 0.7, 1.8
2.5, 0.5, 1.4
2.5, 1.0, 0.5
17, 13, 48
13, 17, 6.7
3.2, 7.5, 13
6.5, 16, 21
8.6, 13, 15
19, 7.2, 14
4.2, 7.2, 8.5
4.7, 2.1, 4.8
17, 16, 28
2.67
3.07
3.09
2.26
2.16
1.71
2.47
2.33
1.58
7.2
b
Nd = not determined.
a
3 mg/kg oral dose.
42% and 97% I @150 and 500 nM respectively.
b
Table 3
SAR at C-8 from leads 15 and 17
R6
R6
R6
N
R6
X
N
N
N
N
N
N
N
NH
NH
NH
NH
R8
N
15,17,27-33
34
40,41
35-39
Compd
R6
R8
X
H+/K+ ATPase pIC50
Rat H+ secretion%I (3 mg/kg po)
CYP IC50
(lM) 2C9, 3A4 (DEF, 7BQ)
CHI log D pH 7.4
15
17
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
2-Pyridone
1,2,4-Triazole
2-Pyridone
1,2,4-Triazole
2-Pyridone
1,2,4-Triazole
2-Pyridone
2-Pyridone
2-Pyridone
2-Pyridone
2-Pyridone
1,2,4-Triazole
2-Pyridone
2-Pyridone
1,2,4-Triazole
2-Pyridone
1,2,4-Triazole
2,6-diCH3
2,6-diCH3
2-CH3
2-CH3
2-Cl-4-F
2-Cl-4-F
H
2-MeO
3-Me
—
—
—
—
—
—
—
—
—
7.9
7.6
7.2
6.3
7.0
6.3
5.8
5.3
4.7
<4
7.1
6.9
5.6
6.4
6.8
6.2
6.6
93d
92
68
Nd
57
76
Nd
Nd
Nd
Nd
100
92
17, 13, 48
13, 17, 6.7
10, 7.2, 17
2.9, 17, 3.8
3.7, 3.4, 13
1.1, 5.2, 2.9
13, 19, 24
5.6, 4.6, 4.2
Nd
2.67
3.07
2.11
2.30
2.26
2.61
1.87
1.93
2.17
0.73
2.33
2.72
2.36
1.55
1.71
3.35
2.27
—
—
Nd
—
—
—
—
Ha
Ha
Hb
OHc
OHc
23, 13, 36
4.6, 5.1, 5.5
2.5, 18, 86
97, 62, >100
5.3, 3.1, 15
5.6, 7.7, Af
14, 0.7, 2.6
44
84e
Nd
Nd
Nd
—
—
—
Nd = not determined.
a
(R) Isomer.
(S) Isomer.
Most active trans isomer.
84% at 1 mg/kg.
21% at 1 mg/kg.
Enzyme activation.
b
c
d
e
f

N. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3602–3606
3605
Table 4
Influence of the C-8 linker
O
N
N
N
X
15, 42-43
Compd
X
H+/K+ ATPase pIC50
Rat H+ secretion %I (3, 1 mg/kg po)
Cli (r,h,d) ml/min/g liver
CYP IC50
(
lM) 2C9,3A4 (DEF, 7BQ)
CHI log D pH 7.4
15
42
43
NH
O
CH2
7.9
7.4
5.9
93, 84
81, 41
nd
6.0, 1.0, 1.9
15, 0.5, 4.4
42, —, 24
17, 13, 48
21, 9.2, 21
4.2, 10, 31
2.67
2.12
2.61
1 and 2. We were encouraged to find that some also gave good
inhibition of pentagrastin-stimulated acid secretion in the rat
following oral administration.8 It was clear that good in vivo activ-
ity required good H+/K+ ATPase and parietal cell inhibitory activity
as well as good in vivo blood concentrations.
It is also apparent from Table 1 that: (a) CYP450 liabilities
(mainly 2C9 and 3A4) are associated with compounds of higher
CHI log D,9 (b) reducing (e.g., 12) or increasing (e.g., 16) CHI log D
too far results in poor cellular penetration and so poor parietal cell
inhibition, (c) there is a cross-species difference in magnitude of
intrinsic clearance, (d) the lowest rat blood concentrations follow-
ing oral dosing are largely associated with the highest intrinsic
clearance, (e) intrinsic clearance differences are driven partly but
not solely by CHI log D differences—this may also result from liabil-
ities due to some of the substituents themselves, or to less benefi-
cial electronic effects on the overall template.
We next investigated the SAR of the two overall best molecules,
15 and 17, seeking to optimize further their physicochemical prop-
erties. We initially looked at close analogues of the C6-pyridone or
triazole, respectively (examples are shown in Table 2), specifically
those bearing substituted 1,2,4-triazoles, substituted 2-pyridones
or close analogues of the 2-pyridone motif. These afford
further evidence that the H+/K+ ATPase enzyme tolerates broad
substitution at C6, and indeed some also give cell and in vivo
potency. Compounds with lowered CHI log D again gave somewhat
improved CYP450 inhibition and intrinsic clearance profiles;
however, if lowered too far (e.g., as in 23 and 26), poor cell
penetration and so poor cell and in vivo acid suppression again
resulted.
None of the modified C6-substituted analogues afforded
improvement over the progenitor 15 or 17. We therefore broadened
our SAR investigation of these two compounds to other positions in
the molecule.
In line with previously published SAR in related systems there
was a strong requirement at C8 for ortho-lipophilic-substituted
phenyl for good enzyme activity (compare 15, 17 and 27–30 with
31–33 as well as 31 with 34) indicating the orthogonal relative ori-
entation of this substituent relative to the heterocyclic scaffold
(Table 3).10
Thus, whilst they reduce CHI log D, replacements for the ortho-
dialkyl substituents were detrimental to in vitro and in vivo
potency, and also gave no additional benefit to CYP450 profiles
(or intrinsic clearance—data not shown). Introducing specific con-
straints via cyclization from the linker nitrogen atom to the poten-
tially metabolically vulnerable benzylic position gave potent
inhibitors in vitro (compare 35, 36 and 38, 39 vs 37) and in vivo
(inhibitor 36) although no improvement in overall profile. Intro-
duction of an hydroxy group (compound 38) improved CYP450
profile as expected due to lower CHI log D, but had a detrimental
effect on in vitro and in vivo potency. Locking the conformation
of the C-8 aryl substituent and blocking the benzylic position alter-
natively via cyclization to the imidazo[1,2-a]pyridine ring (see 40
and 41 as examples) has been reported11 to give potent inhibitors,
but in our hands, resulted in inferior in vitro potency and develo-
pability profiles compared to 15 or 17.
The role of the C-8 linker atom was also investigated. Compounds
withheteroatomlinkersweremoreactivethantheiralkanecounter-
part (Table 4) and also of superior CYP450 and intrinsic clearance
profiles. The difference in profile between 15 and 42 is representa-
tive of what was observed between most NH- and O-linked ana-
logues (data for other compounds not shown) whatever the nature
of the C-6 substituent: despite their lower CHI log D, the latter were
in general of similar CYP450 profiles but had slightly inferior rat and
human intrinsic clearance profiles which may go some way to ex-
plain their poorer in vivo potency.
At the C-2 and C-3 positions very few modifications were toler-
ated (Table 5): our early SAR investigation of 1 suggested that a
methyl substituent at C-2 was essential for good activity (compare
activity of 44 and 1) and introduction of an hydrophilic substituent
at this position was poorly tolerated (compare activity of 15 and
45) hence no further modification was attempted in this position.
C-3 Hydroxymethyl (47), hydrogen (46) or halogen (48) were the
only methyl-replacements at this position to give sub-micromolar
in vitro activity (data for other analogues including methoxy-
methyl, carboxy-amides, aminomethyl, not shown).12 46 gave
comparable in vivo activity to 15. The lower CHI log D-hydroxy-
methyl derivative 47 (by analogy with AZD-0865 (1),2a a possible
metabolite of 15) showed inferior in vivo potency.
The compounds which showed the most appropriate overall
profiles were progressed to oral PK studies in rat and dog (Table
6). Despite the differences in in vitro clearance rates, the in vivo
PK data in both rat and dog were in broad agreement with each
other. Oral bioavailabilities were in line with the blood clearance
rates which in turn, together with volumes of distribution, are lar-
gely predicted by CHI log D values. Compound 15 proved to have
the best balance between in vitro and in vivo potency and DMPK
profile.
In summary, the C6-heteroaryl/heterocyclyl-substituted imi-
dazo[1,2-a]pyridine template affords a good start-point for the
identification of gastric acid suppressing molecules. The overall
developability, cellular potency and in vivo performance of such
molecules can be tuned to a large extent by targeting appropriate

3606
N. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3602–3606
Table 5
SAR at the C-2 and C-3 positions
O
R3
O
N
N
H2N
N
R2
N
N
NH
NH
44
Compd
R2
R3
H+/K+ ATPase pIC50
Rat H+ secretion %I (3, 1 mg/kg po)
1
—
—
—
—
7.0
5.7
7.9
5.4
6.4
6.9
6.1
—, 94
nd
93, 84
nd
92, 90
90, 27
nd
44
15
45
46
47
48
CH3
CH2OH
CH3
CH3
CH3
CH3
CH3
H
CH2OH
Cl
Table 6
In vivo pharmacokinetic data for selected APAs
CLba (mL/min/kg)
Rat (n = 1 or 3)* Dog (n = 1 or 3)*
21 8c
Vssa (L/kg)
T1/2 (h)
Fpob (%)
a
Compd
Rat
Dog
Rat
Dog
Rat (n = 3)
Dog (n = 3)
15
17
21
35
46
47
48 2c
83 16
55
1.3 <0.1
3.5 1.4
1.5
3.7 0.9
6.6 0.8
0.5 <0.1
nd
0.5
0.3
0.5
2.5 0.4
2.3 0.2
33
21
5
3
61 28
50
7
12
5
13 11
nd
90
58
1.8
1.8
18
28
6
9
37
2
10
1.0 0.1
1.1
5.3
1.6
36
a
1 mg free base/kg/h iv dose (solution in 0.9% w/v saline containing 10% w/v hydroxylpropyl-b-cyclodextrin and 2% v/v DMSO).
3 mg free base/kg p.o. dose (suspended in 1% w/v methylcellulose).
iv formulation: 0.9% w/v saline.
b
c
*
Standard deviations given when n = 3.
6. For related work, see: (a) Palmer, A. M.; Grobbel, B.; Jecke, C.; Brehm, C.;
physicochemical properties. As a result we have succeeded in iden-
tifying compounds which inhibit acid secretion at low oral doses in
the rat with good in vitro and in vivo DMPK profile in both rat and
dog. Amongst them, inhibitor 15 proved to have the best overall
profile. Further acid suppression studies and characterization of
this derivative will be reported in due course.
Zimmermann, P. J.; Buhr, W.; Feth, M. P.; Simon, W.-A.; Kromer, W. J. Med.
}
Chem. 2007, 50, 6240; See also (b) Palmer, A. M.; Munch, G.; Brehm, C.;
Zimmermann, P. J.; Buhr, W.; Feth, M. P.; Simon, W.-A. Bioorg. Med. Chem. 2008,
16, 1511. and references cited therein.
7. The conditions of reactions were identical to conditions (i), Scheme 1.
8. Typically groups of male Wistar rats weighing 150 20 g are fasted overnight
prior to use in groups of 3. Test substance or vehicle (2% tween80 + 98% water)
is administrated by oral gavage at 60 min before challenge with pentagastrin
References and notes
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Hepatol. 2007, 5, 1385–1391. and references cited therein.
9. This trend was observed with most of the compounds in this series, hence only
IC50s against 2C9, 3A4 DEF and 7BQ are reported in the rest of the manuscript.
10. For first report of SAR in the imidazo[1,2-a]pyridine series, see: 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.
11. (a) Kaminski, J. J.; Doweyko, A. M. J. Med. Chem. 1997, 40, 427–436; (b)
Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson, B.-M. J. Med. Chem. 1991,
34, 533–541. Compounds 40 and 41 were obtained from the corresponding
chiral C-6 Bromo derivative (most potent isomer obtained by chiral
chromatography from the racemic mixture). See: Buhr, W.; Zimmermann, P.
J.; Brehm, C.; Palmer, A.; Kromer, W.; Postius, S.; Simon, W.-A. PCT Int. Appl.,
WO 2005077949A1, 2005 and references cited therein
3. Andersson, K. Society for Medicines Research Symposium, September 21,
London, UK, 2006.
4. 3A4 DEF assay uses Diethoxyfluorescein as CYP 3A4 substrate. The 3A4 7BQ
assay uses 7-Benzyloxyquinoline.
12. The same trend is observed in the C-6 triazole series (data not shown).
Kaminski et al. have reported activity with a –CH2–CN or NH2 groups but have
shown that these substituents can lead to liver toxicity: see Kaminski, J. J.;
Perkins, D. G.; Frantz, J. D.; Solomon, D. M.; Elliott, A. J.; Chiu, P. J. S.; Long, J. F. J.
Med. Chem. 1987, 30, 2047–2051. and references cited therein.
5. The active form of the inhibitor is known to be the protonated imidazopyridine
and the pIC50 determination is done at pH 7.4. See: (a) Wallmark, B.; Briving, C.;
Fryklund, J.; Munson, K.; Jackson, R.; Mendlein, J.; Rabon, E.; Sachs, G. J. Biol.
Chem. 1987, 262, 2077; (b) Briving, C.; Andersson, B.-M.; Nordberg, P.;
Wallmark, B. Biochim. Biophys. Acta 1988, 946, 185.