Discovery of AZD2932, a new Quinazoline Ether Inhibitor with high affinity for VEGFR-2 and PDGFR tyrosine kinases

Article abstract of DOI:10.1016/j.bmcl.2011.11.019

A new series of Quinazoline Ether Inhibitor which potently inhibits VEGFR-2 and PDGFR tyrosine kinases is described here. In vitro, pharmacokinetics and in vivo evaluations led to the selection of AZD2932.

Full text of DOI:10.1016/j.bmcl.2011.11.019

Bioorganic & Medicinal Chemistry Letters 22 (2012) 262–266
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of AZD2932, a new Quinazoline Ether Inhibitor with high affinity
for VEGFR-2 and PDGFR tyrosine kinases
Patrick A. Plé a, , Frédéric Jung a, , Sue Ashton b, Laurent Hennequin a, Romuald Laine b, Rémy Morgentin a,
⇑
⇑
Georges Pasquet a, Sian Taylor b
a AstraZeneca, Centre de Recherches, B.P. 1050, 51689 Reims Cedex 2, France
b AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of Quinazoline Ether Inhibitor which potently inhibits VEGFR-2 and PDGFR tyrosine kinases
is described here. In vitro, pharmacokinetics and in vivo evaluations led to the selection of AZD2932.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 11 October 2011
Revised 4 November 2011
Accepted 6 November 2011
Available online 12 November 2011
Keywords:
VEGF
PDGF
Inhibitors
VEGFR-2 (also known as KDR) is a member of the Class V receptor
tyrosine kinase (RTK) family, along with VEGFR-1 (Flt-1) and VEG-
Aurora inhibitory activity.8 This series led to AZD1152 (Fig. 1)
which is currently in phase II.
FR-3 (Flt-4). Structurally related are PDGFR
a
, PDGFRb, c-Kit and
The compounds described here were synthesized as shown in
Schemes 1 and 2 and experimental details for their syntheses can
be found in the references given therein. Aurora activity relied on
a lipophilic acetanilide right hand side linked by an aminopyrazole
group at C-4 of the quinazoline (e.g., 1 has an IC50 against Aurora B
of <0.2 nM). In contrast to the Aurora kinases, it was quickly found
that PDGFRb tolerated more hydrophilic side chains giving excel-
Flt-3, which are members of the class III RTK family. VEGFR-2 is
primarily expressed on vascular endothelial cells and plays a key
role in angiogenesis within both normal tissue and solid tumors.1
PDGFRb is expressed on pericytes, a cell type involved in the matu-
ration and stabilization of newly formed blood vessels.2,3 PDGFR
a
and/or PDGFRb may also be expressed by tumor-associated fibro-
blasts. Inappropriate PDGFR and PDGFRb signaling has been linked
a
lent selectivity versus Aurora B (2 and 3 IC50 >0.01 lM) and that
to a number of proliferative disorders, gastrointestinal tumors
(GIST) dermatofibrosarcoma protuberans (DFSP), idiopathic hype-
reosinophilic syndrome (HES) and chronic myelomonocytic leuke-
mia (CMML) and a sub-set of high-grade glioma.4 VEGF signaling
inhibitors such as Avastin have already shown efficacy in the clinic
as well as multi-targeted kinase inhibitors such as Sutent (which
inhibits PDGFRb, VEGFR-2 and other kinases). Selective inhibition
of both VEGFR-2 and PDGFRb could have significant anti-tumor
activity through effects on tumor vasculature. Thus, our aim was
to identify a compound with similar potency against both PDGFR
and VEGFR-2 to maximize efficacy as an anti-angiogenic therapy.
The quinazoline family of kinase inhibitors has been extensively
studied at AstraZeneca and has led to Vandetanib,5 Cediranib6 and
AZD05307 which are currently launched or in clinical trials. More
recently we discovered a novel series of quinazolines with acetan-
ilide substituted 5-membered rings at C-4 possessing potent
replacement of the amino group by an ether linker was beneficial
for both PDGFRb and VEGFR-2 inhibition (5 vs 4 and 6 vs 2). Com-
pound 6 was highly potent against both enzymes and was used to
probe substitution at positions 5, 6 or 7 on the quinazoline ring.
Introduction of a neutral side chain in C-6 or C-7 retained the same
profile while substitution in C-5 was detrimental versus VEGFR-2
(6, 8, 11). Basic side chains introduced at C-6 or C-7 (9, 10) gave
potent inhibitors of both receptors but suffered from high in vivo
O
H
N
H
N
N
HN
N
5
4
N
O
6
F
HO P
O
HO
N
O
7
⇑
Corresponding authors.
E-mail address: patrick.ple@astrazeneca.com (P.A. Plé).
Figure 1. Structure of AZD1152.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.019

P. A. Plé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 262–266
263
N
COOH
N
R5
Cl
Y
N
R6
R7
R6
R7
xv or xvi
X
N
N
I
4,8,9
I
X
R5
R6
R7
ref
a
b
c
d
e
f
g
h
N
C
C
N
N
N
N
N
H
OMe
OMe
9
10
10
9
H
CN
OMe
H
OMe
H
OMe
OMe
OMe
H
OMe
O(CH2)2OMe
9
H
H
H
O(CH2)2OMe
O(CH2)2N(CH2)5
OMe
OMe
OMe
O(CH2)2N(CH2)4 11
i
ii
vi, vii
or viii, vii
or ix
xi, or
xii, or
xiii
xiv
iii, iv
N
N
COOH
COOH
COOH
HN
N
COOH
R5
O
Y
Y
N
O
R6
R7
MeO
MeO
MeO
MeO
MeO
MeO
X
X
N
N
N
N
III
II
II
a
a
b
c
d
e
f
Y
ref
III
a
Y
O
N
O
ref
12
13
O
N
O
O
O
O
O
O
O
9
a
10
10
9
c
v
v or x
v or x
x
9
g
h
9
O
H
N
N
N
CONHAr
CONHAr
O
HN
N
R5
NH
O
Y
X
N
Y
O
N
R6
R7
N
MeO
MeO
MeO
MeO
MeO
MeO
N
X
N
MeO
N
N
15
1-3, 5-7, 10-14
16-18, 26-33
19
Scheme 1. Reagents and conditions: (i) 4-chloro-7-methoxyquinazolin-6-ol,14 2-methoxyethanol, PPh3, di-tert-butyl azodicarboxylate, CH2Cl2, rt, 2 h, 60%; (ii) 4-chloro-7-
methoxyquinazolin-6-ol,14 2-(1-piperidyl)ethanol, PPh3, di-tert-butyl azodicarboxylate,, CH2Cl2, rt, 14 h, 86%; (iii) methyl 2-(5-hydroxy-1H-pyrazol-3-yl)acetate,15 DMAP,
PhCl, 130 °C
hydroxypyrazol-1-yl)acetate9,10 NaH, DMF, 60 °C, 0.5 h, 90%; (vii) TFA, CH2Cl2/H2O (5%), rt, 1 h, 100%; (viii) (X = C; X = N, R7 = O(CH2)2OMe; X = N, R5 = OMe; X = N,
7 = O(CH2)2 N(CH2)4) tert-butyl 2-(4-hydroxyphenyl-1-yl)-acetate, K2CO3, DMA, 90 °C, 18 h, 27% -91%; (ix) 2-(4-aminopyrazol-1-yl) acetic acid,16 isopropanol, 80 °C, 1 h,
lW, 1 h, 45%; (iv) NaOH, MeOH, H2O, rt, 4 h, 69%; (v) ArNH2, 2-hydroxypyridine N-oxide, EDCI, DIEA, DMF, 55 °C, 12 h; (vi) (X = N; X = C, R6 = CN) tert-butyl 2-(4-
R
87%; (x) Ar NH2, HATU, DIEA, DMF, 60 °C, 2 h; (xi) (X = N) 4-hydroxyphenylacetic acid, K2CO3, DMF, 90 °C, 4 h, 86%, (xii) 4-aminophenylacetic acid, isopropanol, HCl (5 N) cat;
80 °C, 2 h, 90%; (xiii) (X = C) 4-hydroxyphenylacetic acid, Cs2CO3, DMF, 150 °C, 7 h, 81%; (xiv) 3-hydroxyphenylacetic acid, K2CO3, DMF, 90 °C, 2 h, 75%;(xv) 2-(4-
aminopyrazol-1-yl)-N-(5-dimethylaminopyridin-2-yl)acetamide,16 K2CO3, DMA, 100 °C
K2CO3, DMF, 70 °C, 2.5 h, 80%.
l
W, 5 min, 40%; (xvi) 2-(4-hydroxypyrazol-1-yl)-N-(3-methoxyphenyl)acetamide9,10
clearance in rat with consequently short iv t1/2 and poor bioavail-
ability (e.g., 9 gave respectively 75 ml/min/kg; 0.4 h and 9%).
Replacement of the quinazoline core by a quinoline (6 vs 13) signif-
icantly reduced VEGFR-2 activity while a central 3-O-pyrazole ring
(15) completely annihilated activity against both kinases. In
general the compounds synthesized in this series had moderate
selectivity versus CSF-1R but little or none versus Flt-3 and c-Kit
(data not shown).
The ether pyrazole series I had some drawbacks such as their
relative instability at low pH (as low as 0.1 day at pH 1 at 25 °C)
due to hydrolysis at the C-4 and loss of the pyrazole fragment as
well as modest rat PK parameters, especially bioavailability
(<20%). For these reasons we turned our attention to the phenyl
ether series.
rat while retaining excellent potency against both PDGFRb and
VEGFR-2 (compare 6 and 17; 5 and 16; 14 and 30), albeit with
an increase in LogP of about 1 unit. Similar to the pyrazole series,
the C-4 aminoquinazolines were substantially less potent than
the corresponding ethers (17 vs 18 and 32 vs 33). Modifications
and changes in the position of the amide linker were also investi-
gated. Introduction of the side chain in meta rather than para
position of the phenyl ring was detrimental (19) as were the
replacement of the para-acetanilide by an urea (20), a sulfonamide
(21), a reversed amide function (22) or a benzamide (23). The only
modifications which retained activity against PDGFRb were the
reverse acetanilide (24) and the ether (25), but in both cases
VEGFR-2 inhibition was lost.
Many substituted aromatic and heteroaromatic rings were
introduced on the right hand side of the molecule to modulate
the PDGFRb:VEGFR-2 ratio as well as the physical properties.
Replacement of the pyrazole by a phenyl ring allowed us to
improve the chemical stability, as well as the PK parameters in

264
P. A. Plé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 262–266
Cl
MeO
N
MeO
ii, iii
N
i
viii, iii
x
O
COOH
NH2
OMe
NH2
O
N
O
N
O
N
O
N
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
25
iv, v or
vi or
vii
xi
ix
O
O
OMe
L
NH
NH
OMe
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
OMe
N
N
N
N
N
N
20-22
23
24
Scheme 2. Reagents and conditions12: (i) 4-[(3-methoxyphenyl)methoxy]phenol, Cs2CO3, DMA, 90 °C, 1 h, 64%; (ii) tert-butyl N-[(4-hydroxyphenyl)methyl]carbonate, K2CO3,
DMA, 140 °C, 1 h, 92%; (iii) TFA, CH2Cl2, rt, 1 h, 97%; (iv) 4-nitrophenyl chloroformate, CH2Cl2, DIEA, rt, 2 h, 100%; (v) 3-methoxyaniline, CH2Cl2, 45 °C, 48 h, 13%; (vi) 3-
methoxybenzenesulfonyl chloride, CH2Cl2, DIEA, rt, 1 h, 62%; (vii) 3-methoxybenzoic acid, HATU, DIEA, DMF, rt, 2 h; (viii) tert-butyl 4-hydroxybenzoate, DMA, K2CO3, 100 °C,
2 h, 90%; (ix) 3-methoxybenzylamine, O-benzotriazol-1-yl-N,N,N’,N’-tetramethyluronium tetrafluoroborate, DIEA, DMA, rt, 12 h, 86%; (x) 4-aminophenol, NaH, THF/DMF,
80 °C, 1 h, 83%; (xi) 2-(3-methoxyphenyl)acetylchloride, CH2Cl2, Et3 N, rt, 2 h, 56%.
Among these, the pyrazoles were found to be the most interesting
series (26–33). Alkylation of the 3-aminopyrazoles in C-5 gave po-
tent inhibitors against both kinases while N-1 alkylation severely
reduced their activity, especially against VEGFR-2 (26 vs 27). The
opposite was true with the 4-aminopyrazoles: N-1 alkylation
substantially increased potency (compare NH pyrazole 28 with
29, 30 and 32). Interestingly, in both series, incremental increase
of lipophilicity led to increased potency against PDGFRb, and even
more so against VEGFR-2 activity. Fine-tuning of the lipophilicity
of the pyrazole series led to the discovery of 32 with a balanced
ꢀ1:1 ratio of activity vs both VEGFR-2 and PDGFRb.
exposure was linear with dose, 20 mg/kg being the top one used
(Table 2).
For both sexes the clearance was low (10% of hepatic blood
flow), the mean steady state volume of distribution was 0.9 l/kg,
thus giving a terminal iv half-life of 4.2 h. When oral doses above
10 mg/kg were used, the profile of the plasma concentration versus
time became highly variable. Because dissolution rate and solubil-
ity were considered to be major contributing factors to this issue, a
salt form of AZD2932 was investigated.
The bis-(dihydrogenphosphate) salt of 36 was found to be the
best in terms of crystalinity and low hydroscopicity and gave a
15-fold increase in dissolution rate over the free base. Using this
salt in a corn oil formulation p.o. gave almost complete bioavail-
ability in both rats and dogs (Table 2) and improved the consis-
tency of the absorption/elimination phases between dogs.
The risk of generating an Ames positive amine upon cleavage of
the amide bond was recognized early on and all interesting amines
were therefore tested for this. A number of compounds fell for this
reason alone. The 3-methoxyaniline was Ames positive but this
aniline was used extensively in the initial phases of the program
to build up SAR. The N’,N’-dimethylpyridine-2,5-diamine of 16,
the 4-aminopyrazoles of 29, 30, 32 and the 5-ethyl-1H-pyrazol-
3-amine of 26 were devoid of Ames risk but the positional pyrazole
isomer of 27 was found to be mutagenic.
Taking into account these considerations as well as in vivo
parameters, compound 32 was finally chosen as our development
candidate AZD2932.
AZD2932 has a potent and balanced profile against PDGFR, VEG-
FR-2, Flt-3 (Table 1) and c-Kit (IC50: 0.009). It does not inhibit the
various cytochrome P450 isoforms with the worst IC50 being
All of our compounds potently inhibited both PDGFR
PDGFRb phosphorylation with a correlation close to 1:1 and
AZD2932 was no exception ( : 2 nM; b: 4 nM). PDGFR-related
a and
a
pharmacodynamic activity was assessed ex-vivo by western blot-
ting of lysates from C6 rat glial tumors grown subcutaneously in
athymic mice. In vitro and ex-vivo studies on C6 cells and tumors
showed PDGFR
were thus used as a surrogate for PDGFRb in vivo. Single bolus oral
doses of AZD2932 resulted in dose-related inhibition of PDGFR
a to be constitutively active on this cell line and
a
phosphorylation 6 h after dosing which correlates with free plasma
concentrations (Fig. 2).
against 2C9 (8.0
3.3% free in human and 7.0% in dog sera and has no activity against
hERG (IC50 137 M).
In rat the clearance was about 6% hepatic blood flow and is
consistent with the low in vitro metabolic clearance (3.5 l/min/
l
M). It has a good fraction unbound between
Inhibition of PDGFRa phosphorylation was also time dependent
with a single dose administration of 3 mg/kg achieving inhibition
l
of the target for ꢀ10 h (Fig. 3).
The same C6 in vivo model was used to study tumor growth
inhibition (TGI) with AZD2932. Twice daily oral dosing (b.i.d.)
10 h apart resulted in significant TGI of 64% for both 50 and
12.5 mg/kg doses on the day the control animals were terminated
l
million cells). The mean steady state volume of distribution in male
rats was 0.8 l/kg with a terminal iv half-life of 1.3 h. Increase of

P. A. Plé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 262–266
265
Table 1
In vitro SAR (IC50
lM)
O
H
L-Ar
N
N
N
O
N
N Ar
H
Ar
R5
Y
N
N
H
O
N
Y
N
O
N
N Ar
H
4
X
R6
R7
MeO
MeO
O
MeO
MeO
MeO
MeO
N
X
1,4-pyrazole (Series I)
3,5-pyrazole (Series II)
1,4-Phenyl (Series III)
1,3-Phenyl (Series IV)
#
X
Y
Series
L
Ar
R5
R6; R7
Receptor phosphorylation in cell
PDGFRb
VEGFR-2
CSF-1R
Flt-3
1
2
3
4
5
6
7
8
9
N
N
N
N
N
N
N
N
N
N
N
C
N
N
N
N
O
O
O
O
O
O
O
O
O
O
I
I
I
I
I
I
I
I
I
I
I
I
I
I
II
III
III
III
IV
III
III
III
III
III
III
III
III
III
III
III
III
III
III
Ph-3-F
Ph-3-OMe
Ph-4-N(Me)2
2-Pyridin-5-N(Me)2
2-Pyridin-5-N(Me)2
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
4-Pyrazol-1-Et
4-Pyrazol-1-Et
2-pyridin-5-N(Me)2
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
Ph-3-OMe
3-Pyrazol-5-Et
3-Pyrazol-1-Et
4-Pyrazole
4-Pyrazol-1-Me
4-Pyrazol-1-Et
4-Pyrazol-1-Et
4-Pyrazol-1-iPr
4-Pyrazol-1-iPr
MeO; MeO
MeO; MeO
MeO; MeO
MeO; MeO
MeO; MeO
MeO; MeO
MeO; MeO(CH2)2O
MeO(CH2)2O; MeO
(CH2)5N(CH2)2O; MeO
MeO; (CH2)4N(CH2)2O
H; MeO
CN; MeO
MeO; MeO
MeO; MeO
0.010
0.010
0.006
>0.2
0.051
0.025
0.101
0.453
0.039
0.0004
0.0002
<0.005
0.031
0.007
0.030
0.282
0.057
0.035
>10.0
0.022
0.008
0.175
1.009
0.177
>10.0
6.144
3.063
0.209
0.128
<0.005
0.172
>10.0
0.667
0.029
0.012
0.008
0.485
>1
0.004
>0.02
0.004
0.010
0.003
0.002
0.002
0.003
0.010
0.005
0.005
0.040
0.020
0.004
>1
>0.9
0.600
>1
0.003
0.0008
0.0003
0.002
0.003
0.001
0.002
0.002
0.002
0.004
>1
0.005
0.0009
0.010
0.300
0.009
>1
0.300
0.700
0.004
0.020
0.004
0.010
>2
0.040
0.003
0.0004
0.004
0.020
0.020
0.010
0.008
0.090
0.400
0.03
0.100
0.05
0.04
0.200
>1
0.600
0.300
>1
>1
>1
>1
>1
>1
0.03
0.300
>0.6
>1
>1
>1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
OMe
C
N
N
N
N
O
O
N
CH2CONH
CH2CONH
CH2CONH
0.009
0.007
>0.06
>1
0.008
>1
N
N
N
N
N
N
N
N
N
N
N
C
O
O
O
O
O
O
O
O
O
O
O
O
O
N
CH2NHCONH
CH2NHSO2
CH2NHCO
CONHCH2
NHCOCH2
OCH2
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
>1
>0.4
0.010
0.020
0.005
0.020
>0.8
0.080
0.010
0.004
0.007
0.020
>0.8
0.040
0.100
>1
N
N
Table 2
120
100
80
60
40
20
0
1
pPDGFR-alpha
AZD2932 DMPK parameters in rat and dog
Free plasma
concentration (uM)
Free base
Phosphate salt
0.1
Rat
Dog
Rat
Dog
Dose
Cl
Vdss
IV t1/2
PO t1/2
Bioavail.
mg/kg
ml/min/kg % HBF
l/kg
H
H
2
2
3.3 9
0.9
2.7
—
3 (iv) 10 (po)
1.7 5.2
0.7
8.9 6a
0.8
0.01
0.001
0.0001
—
—
1.3
6
4.2
4.7
6.8
4.3
>90
6.8
>90
%
34–155b
23–119b
a
Mean Cl from three studies at the dose range of 0.5–2 mg/kg, males only.
Range for p.o. doses of 2–5 mg/kg.
b
50
25
12.5
6
3
1
0.5
AZD2932 dose (mg/kg)
(day 22 on the graph). Significant difference between 50 and
12.5 mg/kg appeared only later (Fig. 4). The difference between
once daily dosing, which gave little TGI, and b.i.d. dosing suggests
that inhibition of target receptors for more than 20 h is required for
activity in this model. Most importantly, xenografts bearing
non-PDGFR expressing tumor cells were also sensitive to
AZD2932 treatment: growth of Calu-6 tumor was inhibited by
Figure 2. PK/PD dose response in nude mice bearing C6 rat glial tumors.
81% and 72% at 50 and 12.5 mg/kg b.i.d. (p <0.001) and LoVo
tumors by 67% at 50 mg/kg b.i.d. (p <0.001). This is due AZD2932
potent activity against VEGFR-2 as well as a potential effect on

266
P. A. Plé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 262–266
120
100
80
60
40
20
0
1.0000
0.1000
0.0100
0.0010
In order to confirm that AZD2932 had similar potency against
pPDGFR-alpha
both PDGFRb and VEGFR-2 phosphorylation in vivo, the female
nude mice bearing C6 tumors from the above experiment were
dosed iv with VEGF-A and PDGFBB 5 min prior to cull and 6 h post
last dose of AZD2932 and the lungs excised immediately after.
Lung lysates were analyzed by western blot for total and phosphor-
ylated VEGFR-2 and PDGFRb. AZD2932 at 3–50 mg/kg b.i.d. 10 h
apart gave 60–80% inhibition of both p-VEGFR-2 and p-PDGFRb
in a 1:1 ratio (Fig. 5).
In conclusion, we have found new and potent inhibitors of
PDGFR and VEGFR-2 phosphorylation out of which AZD2932 was
selected. This compound has shown potency in inhibiting PDGFR
and VEGFR-2 phosphorylation, along with c-Kit and Flt-3, and good
selectivity against a number of other RTKs. The pharmacokinetic
profile along with in vitro potency correlated with both PD and
anti-tumor efficacy in the C6 model. Alongside on going pre-clini-
cal evaluation, these data indicate that AZD2932 has the potential
to become an anti-angiogenic agent in the clinic, through the inhi-
bition of PDGFR and VEGFR-2 signaling.
Free plasma conc (uM)
6
8
10
12
6
8
10
12.5mg/kg
3mg/kg
Time (h) post dose of AZD2932
Figure 3. PK/PD time course in nude mice bearing C6 rat glial tumors.
2.0
Vehicle control
50mg/kg BID
Acknowledgments
12.5mg/kg BID
1.5
3mg/kg BID
We would like to acknowledge the excellent technical expertise
of the following scientists: In vitro and in vivo biology: Claire Barnes,
Nicola Broadbent, Hannah Burn, Lee Cooper, Jack Dawson, Karen
Malbon, John Stawpert, Zena Wilson, Linda Yarwood; Chemistry:
Alain Bertrandie, Myriam Didelot, Maryannick Lamorlette, Mickael
Maudet, Marie-Jeanne Pasquet; NMR: Christian Delvare; Pharmaco-
kinetics: Mike Hutton, Pamela Smith; Physical chemistry: Delphine
Dorison-Duval; Robotic synthesis: Patrice Koza, Jacques Pelleter;
Large scale lab: Harj Bansal, Dominique Boucherot, Stephen Brook,
Ben McKeever, Walter Grundy and Fabrice Renaud.
1.0
0.5
0.0
0
5
10
15
20
25
30
35
References and notes
Days dosed
1. Reviewed in Carmeliet, P. Oncology 2005, 69, 4.
Figure 4. AZD2932 dosed orally in tumor growth study in nude mice bearing C6 rat
2. Abramsson, A.; Lindblom, P.; Betsholtz, C. J. Clin. Invest. 2003, 112, 1142.
3. Song, S.; Ewald, A. J.; Stallcup, W.; Bergers, G. Nat. Cell Biol. 2005, 7, 870.
4. Reviewed in Ostman, A. Cytokine Growth Factor Rev. 2004, 15, 275.
5. Vandetanib has been approved by the FDA for the treatment of symptomatic or
progressive medullary thyroid cancer in patients with unresectable (non-
operable) locally advanced or metastatic disease.
glial tumors.
120
p-PDGFR beta
p-VEGFR-2
6. Cediranib, a selective VEGFR inhibitor, is in phase II. Drevs, J.; Siegert, P.;
Medinger, M.; Mross, K.; Strecker, R.; Zirrgiebel, U.; Harder, J.; Blum, H.;
Robertson, J.; Jürgensmeier, J. M.; Puchalski, T. A.; Young, H.; Saunders, O.;
Unger, C. J. Clin. Oncol. 2007, 25, 3045.
100
80
60
40
20
0
7. AZD0530 (Saracatanib), a Src inhibitor, is in phase II.
(a) Logie, A.; Jacobs, V.; Fennell, M.; Hargreaves, J.; Westwood, R.; Haupt, N.;
Elvin, P.; Wilkinson, R.; Davies, B.; Green, T.P. 18th EORTC-NCI-AACR. Prague,
2006. Abstract # 617.
(b) Tabernero, J. ASCO 2007, Abstract # 3520.
8. Mortlock, A.; Foote, K. M.; Heron, N. M.; Jung, F. H. J. Med. Chem. 2007, 50, 2213.
9. Plé, P.; Jung, F.H. Patent WO 2006040526, Chem. Abs. 2006, 144, 412531.
10. Jung, F.H. Patent WO 2006040522, Chem. Abs. 2006, 144, 412507.
12. Plé, P.; Jung, F.H. Patent WO 2006040520, Chem. Abs. 2006, 144, 412530.
14. Hennequin, L.F.A. Patent WO 2003064413, Chem. Abs. 2003, 139, 307787.
15. Nielsen, A. T. J. Heterocycl. Chem. 1975, 12, 1233.
50 bid
12.5 bid
Dose AZD2932 (mg/kg)
3 bid
16. Heron, N. M.; Pasquet, G. R.; Mortlock, A. A.; Jung, F. Patent WO 2004094410
Chem. Abs. 2004, 141, 395569.
Figure 5. Inhibition of p-VEGFR-2 and p-PDGFRb in mice lungs by AZD2932 at the
end of the tumor growth experiment.
pericytes and tumor-associated fibroblasts due to PDGFR
a and b
inhibition. Further studies are needed to prove this later point.