The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4- oxoquinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

Article abstract of DOI:10.1016/j.bmcl.2012.04.116

A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin- 3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.

Full text of DOI:10.1016/j.bmcl.2012.04.116

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3879–3883
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxo-
quinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38a MAP kinase inhibitor
for the treatment of inflammatory diseases
⇑
Dearg S. Brown, John G. Cumming , Paul Bethel, Jonathan Finlayson, Stefan Gerhardt , Ian Nash,
Richard A. Pauptit, Kurt G. Pike, Alan Reid, Wendy Snelson, Steve Swallow, Caroline Thompson
AstraZeneca, 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 novel, potent and selective quinazolinone series of inhibitors of p38a MAP kinase has been identified.
Received 3 April 2012
Revised 25 April 2012
Accepted 27 April 2012
Available online 2 May 2012
Modifications designed to address the issues of poor aqueous solubility and high plasma protein
binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate
N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703).
Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies
which showed a switch from DFG ‘out’ to DFG ‘in’ as the inhibitor size was reduced to improve overall
properties.
Keywords:
p38a
Ó 2012 Elsevier Ltd. All rights reserved.
Protein kinase inhibitors
X-ray crystal structure
p38
role in the regulation of pro-inflammatory cytokines including tu-
mour necrosis factor alpha (TNF- ) and interleukin-1b (IL-1b), the
a
mitogen-activated protein kinase (MAPK) plays a critical
and low micromolar inhibition of LPS-stimulated TNF-
whole blood (Table 1) as well as cytokine inhibitory activity in
vivo.6 However aqueous solubility was poor (0.54
M, thermody-
a in human
a
l
excessive production of which has been linked to a variety of
inflammatory processes in a broad range of diseases including
rheumatoid arthritis, psoriasis, inflammatory bowel disease, multi-
ple sclerosis, ischaemia, Alzheimer’s disease, and neuropathic
namic solubility measured in 0.1 M phosphate pH 7.4 buffer at
25 °C for 24 h) and plasma protein binding was rather high (2%
free). In addition we were concerned about the possibility of enzy-
matic cleavage of one or other of the amide bonds in vivo with con-
comitant release of a potentially mutagenic aniline species7 or for
aniline impurities to be carried through the manufacture of the ad-
vanced pharmaceutical intermediate.8
pain.1 The early reports of the biology of p38
a together with the
pyridylimidazole-based inhibitors2 precipitated an enormous ef-
fort from many laboratories to discover and develop drugs utilising
this mechanism.3 The effectiveness of biological cytokine blocking
agents such as etanercept, infliximab, and anakinra in treating
rheumatoid arthritis and other autoimmune diseases4 offered the
O
cyclisation
N
N
S
O
hope that targeting of these cytokines through inhibition of p38
a
H
N
H
N
would provide an oral, small molecule alternative. Disappointingly
however, although a number of compounds from diverse chemical
series have progressed into clinical trials none has yet demon-
O
O
1
strated that inhibition of p38
a can deliver a safe and efficacious
treatment of inflammatory diseases.5
We hypothesised that cyclisation from an amide nitrogen to the
adjacent carbonyl-bearing phenyl ring would retain the planar
conformation of the benzamide while removing one potential ani-
line cleavage product. Previous investigations in the bisamide ser-
ies had also suggested that the terminal heteroarylmethoxy group
could be removed without significant loss in potency and replaced
with basic amine-containing side chains/rings which improved sol-
ubility and plasma protein binding. A 6-N-methyl piperazinyl
group was selected because it is a weakly basic group which should
A previous disclosure from this laboratory described the discov-
ery of a novel series of bisamide inhibitors of p38, exemplified by
compound 1.6 Compound 1 showed potent inhibition of p38 kinase
⇑
Corresponding author.
E-mail address: john.cumming@astrazeneca.com (J.G. Cumming).
Present address: Institute for Chemistry and Biochemistry, Albertstr. 21, 79104
Freiburg, Germany.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.116

3880
D. S. Brown et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3879–3883
Table 1
catalysed hydrogenation also reduced the nitro group which had
Inhibition of p38 kinase and LPS induced TNF-a release in human whole blood (HWB)
and human hepatocyte intrinsic clearance for selected compounds
served as a masked aniline on the other phenyl ring. Formation
of the quinazolinone was achieved by cyclisation with triethylor-
thoformate catalysed by acetic acid. Acylation with the substituted
pyridine acid chloride followed by a second SNAr reaction to install
the morpholino group completed the synthesis of 2. The 2-methyl
quinazolinone analogues 3, 6, 11 and 23 were prepared following
the same sequence but substituting triethylorthoacetate for
triethylorthoformate.
R1
N
O
H
N
R2
N
N
N
O
Compound R1 R2
p38a IC50 HWB IC50 HH CLint
a
a
(nM)
(lM)
(lL/min/
106 cells)
Compounds were tested in vitro for inhibition of human p38
a
enzyme activity and for inhibition of TNF-a in LPS-stimulated hu-
1
2
—
H
—
18
35
1.5
0.42
—
17
man whole blood.9 Initial compounds in the quinazolinone series
(2–4) showed moderate to good potency in the p38 and whole
blood assays, similar to that seen for bisamide 1 (Table 1). Aqueous
2-Morpholino-4-
pyridyl
3
Me 2-Morpholino-4-
pyridyl
H
H
220
3
—
solubility was excellent for these compounds (300–900 lM). Sub-
4
5
6
7
8
3-Morpholinophenyl
Phenyl
89
15
1941
108
65
20
9.0
708
14
29
484
155
108
525
25
181
26
>2200
9.0
0.90
0.64
>50
1.8
3.4
1.4
0.18
9.1
0.50
1.2
4.2
2.9
20
6
—
5
—
<3
<3
—
7
11
—
—
5
—
5
7
<3
—
5
stitution with methyl in the 2- position of the quinazolinone led
to a decrease in activity (2 vs 3). Removal of the methyl on the cen-
tral phenyl ring removed all p38 activity, as was seen for the bisa-
mide series6 (data not shown). These compounds had reasonable
pharmacokinetic (PK) properties but rather high in vitro clearance
in human hepatocytes (Table 1). We next sought to improve PK
properties by reducing the molecular weight to below 500 by (i)
changing the substitution on the benzamide group and (ii) replac-
ing the phenyl with alternative groups. The morpholino group was
found not to be required since the unsubstituted phenyl and its
analogues bearing methoxy, cyano and fluoro substituents at vari-
ous positions were active (5, 7–10, 12–13). Replacement of the
phenyl ring with saturated heterocyclyl or cycloalkyl groups re-
duced activity (14–16) as did 6-membered heteroaryl groups
(17). The SAR for 5-membered heteroaryl groups was interesting
since varying both the nature and the position of the heteroatoms
influenced activity significantly (18, thiazolyl isomers 19–21, 22).
As before, the 2-methylquinazolinones were much less potent than
their unsubstituted analogues (6, 11, 23).
Me Phenyl
H
H
H
H
2-Methoxyphenyl
3-Methoxyphenyl
3-Cyanophenyl
4-Cyanophenyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Me 4-Cyanophenyl
H
H
H
H
H
H
H
H
H
H
H
2-Fluorophenyl
3-Fluorophenyl
4-Tetrahydropyranyl
Cyclobutyl
Cyclopropyl
3-Pyridyl
5-Isoxazolyl
4-Thiazolyl
5-Thiazolyl
1.0
9.0
0.11
1.3
0.73
>50
0.11
12
2-Thiazolyl
3-Furanyl
Me 3-Furanyl
1535
—
a
IC50’s were derived from triplicate measurements whose standard errors were
normally <5% in a given assay.
Representative compounds 5, 10 and 22 were tested in a panel
of 14 other protein kinases. IC50s were in all cases >50 lM showing
the excellent selectivity of this class of compounds for p38.
improve physical properties and because it could be readily intro-
duced in the course of the synthesis.
Quinazolinones 2–23 (Table 1) were prepared as exemplified by
the synthesis of 2 in Scheme 1. The N-methyl piperazinyl group
was introduced by SNAr reaction using the para nitro as an activat-
ing group (step c). Subsequent reduction of the nitro by palladium
Quinazolinones 2 and 22 were co-crystallised with inactivated
p38a and the X-ray structures solved (R = 21.3% for 1.8 Å Dares-
bury synchrotron data and R = 21.1% for 2.3 Å in-house data,
respectively).10 The main features of this binding mode (Fig. 1)
are the hydrogen bond between the amide carbonyl and the back-
bone amide NH of Asp168, the hydrogen bond between the amide
NH and the carboxylate sidechain of Glu71, the good fit between
the methyl-substituted benzene ring and the hydrophobic region
(the so-called ‘selectivity pocket’) formed by residues Lys53 and
Thr106, and the movement of the conserved kinase DFG motif (res-
O2N
O2N
HO
H
a, b
O2N
N
Cl
Cl
O
O
idues 166–170 in p38a
) to the so-called ‘DFG-out’ conformation11
c
to accommodate the morpholino-benzamide group. Compound 2
was the first DFG-out kinase structure determined at AstraZeneca
(around the time of the first literature report of this conformation
for Gleevec bound to abl kinase11c). As such, it spawned significant
internal interest in the inhibition of protein kinases by prevention
of activation.11b The binding mode of 2 is consistent with that re-
ported for the related anilinoquinazoline series12 and with bisa-
mides such as 1. Hence, compounds 1 and 2 are members of the
type II inhibitor class.13 The quinazolinone N1 atom is 3.8 Å from
the backbone amide NH of Met109, compromising the com-
monly-observed hydrogen bond seen here to the hinge region.
The above-mentioned polar interactions to Glu71 and Asp 168 ap-
pear to be dominant, effectively pulling the ligand away from the
hinge. There is a network of hydrogen bonds between the quinaz-
olinone carbonyl, a water molecule, the side chain nitrogen of
Lys53, the amide NH of Ala34 and the amide carbonyl of Asp168.
The binding mode of compound 22 (Fig. 1) shared most of these
features but with one significant difference—the reduced size of
N
O2N
H
d, e
H2N
N
O2N
N
N
N
O
N
O
N
f, g
O
N
N
N
H
N
N
N
O
N
O
2
Scheme 1. Reagents and conditions: (a) (COCl)2, DMF, CH2Cl2, 0 °C to rt; (b) 2-
methyl-5-nitroaniline, NEt3, CH2Cl2, rt (99% over two steps); (c) N-methyl piper-
azine, 100 °C (83%); (d) H2, 10% Pd/C, MeOH, rt (80%); (e) (OEt)3CH, AcOH, EtOH,
70 °C (98%); (f) 2-chloropyridine-4-carbonyl chloride, NEt3, CH2Cl2, rt (91%); (g)
morpholine, 100 °C (57%).

D. S. Brown et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3879–3883
3881
Figure 1. Co-crystal structures of p38a with compound 2 (green, PDB entry 4AA0) and compound 22 (pink, PDB entry 4AA4). Hydrogen bonds are indicated with dashed
lines. See supplementary data for crystal parameters, data collection and refinement statistics.
Table 2
O
O
O
Inhibition of p38 kinase and LPS induced TNF-
for selected compounds
a
release in human whole blood (HWB)
NO2
a, b, c
NH2
HO
N
H
N
O
N
R
d
N
N
N
H
O
O2N
O2N
H
N
O
O
a
a
H
e
Compound
R
p38
a
IC50 (nM)
HWB IC50 (lM)
N
N
N
F
N
H
N
H
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Phenyl
2-Thiazolyl
4-Methyl-2-thiazolyl
5-Methyl-2-thiazolyl
2-(1,3,4-thiadiazolyl)
3-Isoxazolyl
5-Isoxazolyl
Cyclopentyl
Cyclobutyl
Cyclopropyl
347
72
276
>2200
200
6.7
11
692
54
16
156
83
5.4
0.35
12
>50
2
0.011
0.041
11
0.44
0.027
1.4
0.16
1.3
O
N
O
f, g
N
N
N
H
O
N
33
Isopropyl
Ethyl
Methyl
Scheme 2. Reagents and conditions: (a) (COCl)2, DMF, CH2Cl2, 0 °C to rt; (b)
cyclopropylamine, NEt3, CH2Cl2, rt (95% over two steps); (c) H2, 10% Pd/C, EtOH, rt
(94%); (d) 5-fluoro-2-nitrobenzoic acid, HATU, pyridine, DMF, rt (94%); (e) N-methyl
piperazine, DMSO, 80 °C (99%); (f) H2, 10% Pd/C, EtOH, rt (94%); (g) (OEt)3CH, AcOH,
EtOH, 80 °C (79% over two steps).
437
261
Cyclopropylmethyl
2.3
a
IC50’s were derived from triplicate measurements whose standard errors were
normally <5% in a given assay.
the amide group means it no longer induces the DFG loop move-
ment and 22 shows the ‘DFG in’ conformation, making it a type
I½ inhibitor.13 The water molecule is now hydrogen bonded to
the carboxylate of Asp168 rather than the backbone carbonyl.
The quinazolinone N1 atom remains distant from the backbone
amide NH of Met109 (5.4 Å).
potency, while the isopropyl (34) had intermediate potency and
the cyclopropyl (33) was the most potent.15 In their report on a re-
lated series Liu et al.15a rationalise the increased potency of cyclo-
propyl over the ethyl in terms of an increase in the NH hydrogen
bond donor strength.
Reverse-amide quinazolinones 29 and 33 were co-crystallised10
In order to address the one remaining embedded aniline, the ef-
fect of reversing the amide group and replacing the N-substituent
with heteroaromatic and aliphatic groups was investigated. ‘Re-
verse amide’ quinazolinones (Table 2)14 were prepared as exempli-
fied by the synthesis of 33 in Scheme 2.
Reversing the amide bond resulted in compounds which were
active against p38 but the SAR was found to differ markedly from
that observed in the previous quinazolinone series. For example,
with the phenyl substituent (24) reversing the amide led to a drop
in potency, while the 2-thiazolyl (25), 5-isoxazolyl (30), cyclobutyl
(32) and cyclopropyl (33) substituents all gave an increase in po-
tency. Substituting the thiazole ring with methyl resulted in either
a small (26) or large (27) drop in potency depending on the posi-
tion of substitution. The SAR for small alkyl substituents was par-
ticularly striking—going from methyl (36) to ethyl (35) increased
with inactivated p38a and the X-ray structures determined
(R = 23.4% for 2.5 Å ESRF synchrotron data and R = 21.6% for 2.4 Å
in-house data, respectively). The binding modes (Fig. 2) were very
similar to that seen for type I½ compound 22, the main differences
being the presence of an additional bound water molecule hydro-
gen bonded to both the quinazolinone N1 and the Met109 back-
bone NH in 29, and an interaction between the piperazine basic
nitrogen and the amide carbonyl of Val30 in 33.
An analysis of the in vitro data revealed a very good correlation
between the enzyme potency and the potency against LPS-induced
TNF-a in human whole blood corrected for plasma protein binding
(Fig. 3) showing that the improvement from micromolar whole
blood potency seen in bisamide 1 to nanomolar potency seen with
compounds 29 and 33 can be attributed to a reduction in protein
binding. On average there is a drop in activity (ꢀfivefold) going

3882
D. S. Brown et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3879–3883
Figure 2. Co-crystal structures of p38
a
with compound 29 (blue, PDB entry 4AAC) and compound 33 (orange, PDB entry 4AA5). Hydrogen bonds are indicated with dashed
lines. See supplementary data for crystal parameters, data collection and refinement statistics.
Table 4
Additional data for compound 33 (AZD6703)
Human hepatocyte CLint
2 l
L/min/106 cells
Human plasma protein binding
35.7% bound
MWt
417
logD7.4
1.6
pKa
7.6
Aqueous solubility pH7.4
20 g/mL
Caco2 A–B/B–A Papp at 10
CYP450 inhibition IC50
hERG Inhibition IC50
lM
6/11 cm/sec  10À6
>50
>100
>100-fold versus 35 kinases
lM versus 5 isoforms
lM
Kinase panel selectivity
sequential conversion of the two embedded aniline functionalities
in the bisamide series to a quinazolinone and an N-cyclopropyl re-
verse amide, respectively. Introduction of a weakly basic aryl
piperazine group and reduction of molecular weight improved
physical and PK properties and led to improved activity in human
whole blood by reducing plasma protein binding. Structural stud-
ies revealed a switch from ‘DFG-out’ to ‘DFG-in’ modes (hence from
type II to type I½ inhibitors). Taken together these results demon-
Figure 3. Plot of free human whole blood pIC50versus p38a pIC50 with line of best
fit. See supplementary data for data.
from the enzyme IC50 to the calculated free whole blood IC50, as ex-
pected when going from inhibition of the activity in an isolated en-
zyme assay to inhibition of the p38 pathway in cells.
The compounds with the best in vitro properties were profiled
in pharmacokinetic, pharmacodynamic and disease model experi-
ments. Oral absorption was good in rat and dog (Table 3) and the
predicted human PK was consistent with once or twice daily
dosing. The compounds were orally active in vivo in an acute LPS
challenge PD model in rats measuring inhibition of transient circu-
strate that for this class of p38a MAP kinase inhibitors, excellent
potency and selectivity is achievable with type I½ inhibitors while
the additional structural features required for type II inhibitors are
not readily compatible with good physical and oral PK properties.
These investigations culminated in the selection of 33 as
AZD6703 for Phase I clinical studies.
lating TNF-a levels, (ED50 2: 5.6 mg/kg; 29: 0.13 mg/kg; 33: 2.1
mg/kg). Compounds 10 and 33 were active in the Lewis rat strep-
tococcal cell wall arthritis model with ED50 less than 10 mg/kg
once a day.9
Compound 33 progressed through pre-clinical safety testing
and became the Phase I clinical compound AZD6703. Additional
data for 33 is shown in Table 4.
Acknowledgements
The authors would like to thank our colleagues Douglas Camp-
bell, Lucy Ashman, Carol Biddulph, Brian Ellershaw, Karen Burns,
Janet Hayward, Sarah Dawson, Lotta Jansson and Chris Heapy for
developing and carrying out the biological assays, and Dermot
McGinnity, Amanda Berry, Ken Page, Warren Keene and Pauline
Gargan for providing the PK data. Giles Hassall, Jason Breed and
David Hargreaves are thanked for protein purification and crystal-
lization for structural studies.
In summary, a novel, potent, selective and orally available series
of p38
a MAP kinase inhibitors has been discovered through
Table 3
Pharmacokinetic data for selected compounds
Compound
Species
Cl (mL/min/kg)
Vdss (L/kg)
t
(h)
F%
½
Supplementary data
10
10
29
29
33
33
Rat
Dog
Rat
Dog
Rat
Dog
25
36
17
19
26
24
4.8
7.8
2.5
3.7
1.9
3.3
2.9
3.6
1.7
4.0
0.7
1.7
29
53
41
20
49
68
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.04.116.
These data include MOL files and InChiKeys of the most important
compounds described in this article.

D. S. Brown et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3879–3883
3883
9. Brown, D.S. WO 2000055153.
References and notes
10. Protein preparation and crystallisation were described previously11b. See
Supplementary data and PDB depositions 4AA0, 4AA4, 4AAC, 4AA5 as well as
4A9Y for experimental details, crystal parameters, and data collection and
refinement statistics. For general reviews on structural investigations of p38
protein inhibitor complexes see: (a) Karcher, S. C.; Laufer, S. A. Curr. Top. Med.
Chem. 2009, 9, 655. (b) Wrobelski, S.T.; Doweyko, A.M. Curr. Top. Med. Chem.
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