Novel imidazo[1,2-a]pyridine based inhibitors of the IGF-1 receptor tyrosine kinase: Optimization of the aniline

Article abstract of DOI:10.1016/j.bmcl.2011.06.090

Following the discovery of imidazopyridine 1 as a potent IGF-1R tyrosine kinase inhibitor, the aniline part has been modified with the aim to optimize the properties of this series. The structure-activity relationships against IGF-1R kinase activity as well as inhibition of the hERG ion channel are discussed.

Full text of DOI:10.1016/j.bmcl.2011.06.090

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4702–4704
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel imidazo[1,2-a]pyridine based inhibitors of the IGF-1 receptor
tyrosine kinase: Optimization of the aniline
Richard Ducray a, , Clifford D. Jones a, Frederic H. Jung a, Iain Simpson b, Jon Curwen b, Martin Pass b
⇑
a AstraZeneca, Oncology Innovative Medicines, Centre de recherches, Z.I. la Pompelle, 51689 Reims Cedex 2, France
b AstraZeneca, Oncology Innovative Medicines, Alderley Park, Macclesfield, SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Following the discovery of imidazopyridine 1 as a potent IGF-1R tyrosine kinase inhibitor, the aniline part
has been modified with the aim to optimize the properties of this series. The structure–activity relation-
ships against IGF-1R kinase activity as well as inhibition of the hERG ion channel are discussed.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 6 May 2011
Revised 15 June 2011
Accepted 19 June 2011
Available online 25 June 2011
Keywords:
IGF1-R
Insulin-like growth factor-1 receptor
Kinase inhibitor
Inhibition of the Insulin-like Growth Factor-1 receptor tyrosine
kinase has been a growing field of research over the past couple of
years.1 Following up the pioneering clinical studies with antibod-
ies, small molecule kinase inhibitors of IGF-1R are now under eval-
uation in clinical trials and represent a promising approach in the
treatment of a variety of solid cancers.2 In the first part of this
investigation,3 we disclosed the identification of the imidazo
[1,2-a]pyridine 1 (Scheme 1) as a potent inhibitor of IGF-1R with
suitable pharmacokinetic properties for oral administration. We
now wish to report lead optimization work performed through
modification of the aniline substitution and the resulting struc-
ture–activity relationships with regards to inhibition of the IGF-
1R kinase and the ether-a-go-go related gene (hERG) ion channel.
Although compound 1 displays good in vitro activity, as mea-
sured by the inhibition of IGF1 stimulated auto-phosphorylation
of IGF-1R in cell, and good oral pharmacokinetics in pre-clinical
species, the ultimate in vivo efficacy could potentially be limited
by the physical properties of this compound. First of all, a relatively
high protein binding (98.4% in human plasma) balances the in vitro
potency since in vivo efficacy is typically correlated with the con-
centration of the unbound drug. Furthermore, compound 1 has
objective during this work was to retain good selectivity versus
hERG since inhibition of this ion channel has the potential to in-
duce cardiac arrhythmia in patients.
The synthesis of compounds 1–36 has been described in the pat-
ent literature4 and will not be detailed herein. The general proce-
dure to obtain such compounds is summarised on Scheme 1. The
appropriate aniline was condensed with 3-(2,5-dichloropyrimi-
din-4-yl)-imidazo[1,2-a]pyridine5 under acidic conditions in
2-pentanol at a typical temperature of 130 °C. In some instances,
O
N
N
N
N
Cl
N
Cl
Cl
Cl
a
b
N
R
Cl
Cl
N
Cl
N
R
N
N
N
c
NH2
modest aqueous solubility (1.4 lM in a pH 7.4 phosphate buffer)
Cl
O
which is a known cause of limited oral absorption and inter-patient
variability. In order to circumvent this risk, replacement of the
N-acetyl piperazine has been investigated with the aim of either
increasing cellular potency over the lead compound, or improving
the physical properties while maintaining the activity. Another
N
H
N
O
1: R= para-(4-acetyl-piperazin-1-yl)
Scheme 1. General synthesis of compound
1 and analogues. Reagents and
conditions: (a) n-butyl-vinyl ether, Et3N, Pd(OAc)2, PEG-400, 80 °C, 53%; (b) NBS,
dioxane-water, rt, then 2-amino-pyridine, 80 °C, 67%; (c) p-toluenesulfonic acid, 2-
pentanol, 130 °C.
⇑
Corresponding author.
E-mail address: richard.ducray@astrazeneca.com (R. Ducray).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.090

R. Ducray et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4702–4704
4703
the resulting product was further derivatized to provide the desired
compound.
The inhibitory activities of compounds 1–17 against IGF-1R in
our enzymatic and cellular assays as well as the inhibition of the
hERG ion channel in an electrophysiology assay are compiled in
Table 1.6 Replacement of the piperazine ring with a piperidine (2
and de-acetyl analogue 3) led to a similar IGF-1R activity but also
to a moderate hERG inhibition (our objective was to have no signif-
icant hERG inhibition at 33 lM). The piperazinone 4 and the 1-
acetyl-1,4-diazepane 5 were less potent, the latter being also active
in the hERG assay. Introduction of an ether linkage in the form of a
4-oxy-piperidine or a 3-oxy-azetidine (6–9) was also disappointing
as it led to some hERG inhibition, with the exception of compound
8 which unfortunately had a reduced IGF-1R potency. Morpholine
10 displayed a reduced IGF-1R activity in addition to some hERG
inhibition. Homologation of 10 into the benzylamine 11, the benz-
amide 12 or the phenylacetamide 13 led to a further reduction of
IGF-1R activity with no clear beneficial effect on hERG compared
to 10. The 1,3-propanediol derivative 14 had a reasonable activity
against IGF-1R, given the log D reduction induced by the hydroxyl
groups (measured log D 3.1, compared to 3.6 for 1), and showed no
hERG inhibition. However, this compound did not offer any advan-
tage over 1 as it showed a higher plasma clearance and a lower oral
bioavailability in the rat (data not shown).
Table 1
Inhibition of IGF-1R kinase activity and inhibition of receptor autophosphorylation in
cell of compounds 3–10
N
N
R
Cl
N
N
N
O
a
a
Compd
R
IGF-1R IC50
M)
Cell IC50
M)
hERG
(
l
(
l
IC50
, lM
The first improvement in cellular activity was achieved with
compounds 15 and 16 which incorporate a 9-oxa-3,7-diazabicy-
clo[3.3.1]nonane ring, also called oxa-bispidine in reference to the
related bispidine skeleton (3,7-diazabicyclo[3.3.1]nonane) found
in the alkaloids Sparteine and Cytisine.7 The exquisite potency
against IGF-1R of 16 (2 nM in the cellular assay) and its higher frac-
tion unbound in human plasma compared to 1 (5% versus 1.6%) rep-
resented a significant improvement over our lead compound.
However, this was balanced by its ability to inhibit hERG with an
O
O
1
0.009
0.017
>33
N
N
N
2
3
0.006
0.005
0.013
0.009
12
9.1
HN
HN
4
5
0.032
0.023
0.039
0.046
>33
11
N
O
O
IC50 of 1.5 lM. The basicity of 16 is much higher than would be
anticipated based on the inductive effect of the hydroxylethyl
group. Indeed, the measured pKa of 16 (8.4, see Table 2) is much
higher than the value of 6.8 for 4-(hydroxyethyl)-morpholine.8 This
observation can be rationalised by the ability of such a bicycle to
adopt a ‘chair-chair’ conformation in which the lone pair of the phe-
nyl-linked nitrogen stabilizes the ammonium ion ( Fig. 1). This
hypothesis is consistent with a similar effect reported for the parent
bispidine ring.9 In order to find a related bicycle with a reduced
hERG activity, we prepared compound 17 in which the oxa-bispi-
dine moiety is replaced by a 3-oxa-7,9-diazabicyclo[3.3.1]nonane.10
Although this derivative is significantly less basic than its isomer 15
N
N
O
6
0.016
0.017
10
O
N
O
7
8
0.012
0.060
0.046
0.070
4.8
HN
O
O
>33
N
(DpKa = 2.0), this modification only had a minor impact on hERG
O
9
0.057
0.013
0.041
0.026
0.042
0.093
5.9
3.2
9.9
HN
O
Table 2
10
11
N
N
Measured pKa and log D for compounds 15, 16 and 17
a
b
c
Compd
Measured pKa
Measured log D
Log P
O
15
16
17
8.7
8.4
6.7
2.3
2.5
3.0
3.6
3.5
3.1
O
O
12
13
0.060
0.039
0.157
0.112
2.7
8.8
N
N
O
O
a
Measured by UV spectrophotometric titration on
instrument.
a Sirius GLpKa/D-PAS
b
Measured in duplicate using a shake-flask method.
c
Log P = Log D + Log(1+10pKa-7.4).
HO
14
15
16
0.018
0.004
0.004
0.080
0.007
0.002
>33
5.3
1.5
HO
HN
H
+
N
H
H
O
N
O
O
O
N
N
+
N
N
O
N
N
OH
O
R
H
H
R
R
N
17
15
HN
17
0.045
0.082
10
Figure 1. Proposed conformations of the oxa-diaza-bicyclononane rings in com-
pounds 15 and 17. At physiological pH (7.4), 15 is essentially protonated, whereas
17 is present mostly as a free base and its protonated form is likely to adopt the
same conformation.
N
a
IC50 values are means of at least two experiments, standard deviation is less than
2.

4704
R. Ducray et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4702–4704
Table 3
Table 4
Inhibition of IGF-1R kinase activity and inhibition of receptor autophosphorylation in
cell of compounds 3–10
Inhibition of IGF-1R kinase activity and inhibition of receptor autophosphorylation in
cell of compounds
N
N
R
N
R
N
N
Cl
N
N
N
Cl
N
N
O
N
N
O
a
a
Compd
R
IGF-1R IC50
M)
Cell IC50
M)
hERG IC50
M)
(
l
(l
(l
a
a
Compd
R
IGF-1R IC50
M)
Cell IC50
M)
hERG IC50
M)
(
l
(l
(l
O
33
34
35
0.051
0.06
0.141
0.031
0.160
4.3
4.8
5.1
N
N
18
19
20
21
22
23
24
25
26
27
H
0.020
0.015
0.012
0.017
0.009
0.027
0.008
0.011
0.008
0.009
0.020
0.017
0.040
0.035
0.019
0.033
0.249
0.018
0.027
0.047
4.6
3.7
12
9.4
>33
>33
>33
16
CH2CH2OH
CH2CONMe2
CH2CH2SO2Me
SO2Me
CO2Me
CONH2
CONMe2
COCH2OH
(S)-
HN
O
N
O
0.083
N
36
0.12
1.06
1.3
14
8.1
N
O
COCH(Me)OH
(R)-
a
IC50 values are means of at least two experiments, standard deviation is less
28
0.013
0.016
15
than 2.
COCH(Me)OH
COCH2NH2
COCH2NHMe
(S)-
COCH(Me)NH2
(R)-
29
30
31
0.005
0.004
0.005
0.011
0.009
0.009
16
9.5
9.4
and 36 were less active against IGF-1R than their para-counterparts
(10 and 12 respectively) but had a similar hERG IC50
.
In summary, we have explored the structure–activity relation-
ship around our lead compound 1. We have identified compound
16 having a superior IGF-1R inhibitory activity in a cellular assay
and a higher free fraction in human plasma. However this com-
pound showed a higher affinity for the hERG channel, which pre-
cluded its selection as a possible candidate drug.
32
0.006
0.013
14
COCH(Me)NH2
a
IC50 values are means of at least two experiments, standard deviation is less
than 2.
activity (2 fold decrease). This result, in addition to the small differ-
ence in hERG inhibition between compounds 2 and 6 and their basic
analogues 3 and 7, shows the lack of correlation between hERG inhi-
bition and basicity in this series.
Acknowledgments
We would like to thank the following people for their contribu-
tion to the synthesis of the compounds described: Myriam Didelot,
Hervé Germain, Maryannick Lamorlette, Mickael Maudet and Mor-
gan Ménard.
Compound 17 was a less potent IGF-1R inhibitor than 15 (10
fold reduction in enzyme and cellular assays). This is possibly a
consequence of the different shapes of the bicycles as the 3-oxa-
7,9-diaza-bicyclo[3.3.1]nonane is likely to be in a ‘chair-boat’ con-
formation stabilised by an internal hydrogen bond, as opposed to
the ‘chair-chair’ conformation of the oxa-bispidine (Fig. 1). In addi-
tion, the calculated log P values from the measured pKa and log D
(pH 7.4) show a higher intrinsic lipophilicity for 15 compared to
17. This reflects a higher solvation state for the 3-oxa-7,9-diaza-
bicyclo[3.3.1]nonane moiety in water, presumably detrimental to
the ligand affinity for the ATP binding site of the kinase.
The replacement of the piperazine ring in compound 1 having
proved unsuccessful, we pursued our investigation by modifying
the acetyl group (Table 3). The unsubstituted piperazine derivative
18 was as potent as compound 1 but displayed some hERG affinity.
Reducing the piperazine basicity using a nitrogen substituent with
a strong inductive effect (compd 19–21) did not remove hERG
activity. Sulfonamide derivative 22, carbamate 23 and urea 24
were inactive against hERG but only 22 was as potent as 1, while
References and notes
1. (a) Gualberto, A.; Pollak, M. Oncogene 2009, 28, 3009; (b) Gualberto, A.; Pollak,
M. Curr. Drug Targets 2009, 10, 923.
2. (a) Mulvihill, M. J.; Cooke, A.; Rosenfeld-Franklin, M.; Buck, E.; Foreman, K.;
Landfair, D.; O’Connor, M.; Pirritt, C.; Sun, Y.; Yao, Y.; Arnold, L. D.; Gibson, N.
W.; Ji, Q.-S. Future Med. Chem. 2009, 1, 1153; (b) Wittman, M. D.; Carboni, J. M.;
Yang, Z.; Lee, F. Y.; Antman, M.; Attar, R.; Balimane, P.; Chang, C.; Chen, C.;
Discenza, L.; Frennesson, D.; Gottardis, M. M.; Greer, A.; Hurlburt, W.; Johnson,
W.; Langley, D. R.; Li, A.; Li, J.; Liu, P.; Mastalerz, H.; Mathur, A.; Menard, K.;
Patel, K.; Sack, J.; Sang, X.; Saulnier, M.; Smith, D.; Stefanski, K.; Trainor, G.;
Velaparthi, U.; Zhang, G.; Zimmermann, K.; Vyas, D. M. J. Med. Chem. 2009, 52,
7360; (c) Wittman, M. D.; Velaparthi, U.; Dolatrai, M. V. Annu. Rep. Med. Chem.
2009, 44, 281.
3. Ducray, R.; Simpson, I.; Jung, F. H.; Nissink, W.; Kenny, P.; Fitzek, M.; Walker, G.
E.; Ward, L. T.; Hudson, K. Bioorg. Med. Chem. Lett. in press, doi:10.1016/
j.bmcl.2011.06.093.
4. Detailed experimental procedures and 1H NMR characterizations can be found
in the patent application WO-2010/049731.
showing
a lower aqueous solubility (<0.6 lM compared to
5. For the preparation of 3-(2,5-dichloropyrimidin-4-yl)-imidazo[1,2-a]pyridine
see: Ducray, R.; Boutron, P.; Didelot, M.; Germain, H.; Lach, F.; Lamorlette, M.;
Legriffon, A.; Maudet, M.; Ménard, M.; Pasquet, G.; Renaud, F.; Simpson, I.;
Young, G. L. Tetrahedron Lett. 2010, 51, 4755.
1.4 M for 1). Dimethylurea 25 and glycolic or lactic acid deriva-
l
tives 26–28 had some hERG affinity without any IGF-1R activity
improvement over 1. Likewise, compounds derived from glycine,
sarcosine and alanine (29–32) displayed good potency against
IGF-1R but were moderately active in the hERG assay.
Finally, moving the aniline substituent from the para to the meta-
position only provided compounds with inferior properties (Table 4).
Compound 33 was less active than 1 in the IGF-1R assays and dis-
played some affinity for the hERG channel. The unsubstituted piper-
azine 34 had a profile similar to its analogue 18 and compounds 35
6. For
a description of our enzymatic and cellular assays measuring IGF-1R
inhibition see ref.4. IC50 against hERG ion channel have been determined using
the IonWorks electrophysiology platform (Schroeder, K.; Neagle, B.; Trezise, D.
J.; Worley, J. Journal of Biomolecular Screening 2003, 8, 50).
7. Breuning, M.; Steiner, M. Synthesis 2007, 1702.
8. Andrew, C. L.; Klemm, A. R.; Lloyd, J. B. Biochim. Biophys. Acta 1997, 71.
9. (a) Douglass, J. E.; Ratliff, T. J. Org. Chem. 1968, 33, 355; (b) Toom, L.; Kutt, A.;
Kaljurand, I.; Leito, I.; Ottosson, H.; Grennberg, H.; Gogoll, A. J. Org. Chem. 2006,
71, 7155.
10. Revesz, L.; Blum, E.; Wicki, R. Tetrahedron Lett. 2005, 46, 5577.