Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer

Article abstract of DOI:10.1016/j.bmcl.2013.02.056

Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b] pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3- (trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.

Full text of DOI:10.1016/j.bmcl.2013.02.056

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1945–1948
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of AZD3514, a small-molecule androgen receptor
downregulator for treatment of advanced prostate cancer
⇑
Robert H. Bradbury , David G. Acton, Nicola L. Broadbent, A. Nigel Brooks, Gregory R. Carr, Glenn Hatter,
Barry R. Hayter, Kathryn J. Hill, Nicholas J. Howe, Rhys D. O. Jones, David Jude, Scott G. Lamont,
Sarah A. Loddick, Heather L. McFarland, Zaieda Parveen, Alfred A. Rabow, Gorkhn Sharma-Singh,
Natalie C. Stratton, Andrew G. Thomason, Dawn Trueman, Graeme E. Walker, Stuart L. Wells,
Joanne Wilson, J. Matthew Wood
Oncology iMed, AstraZeneca, Mereside, 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:
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduc-
tion of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator
6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed
hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)eth-
oxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), desig-
nated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant
prostate cancer.
Received 10 January 2013
Revised 5 February 2013
Accepted 11 February 2013
Available online 21 February 2013
Keywords:
Prostate cancer
Androgen receptor downregulator
AZD3514
Ó 2013 Elsevier Ltd. All rights reserved.
Prostate cancer is the second leading cause of death from cancer
among men in developed countries, and was projected to account
for 25% of newly-diagnosed cases and 9% of deaths due to cancer in
the USA in 2010.1 The androgen receptor (AR), a ligand binding
transcription factor in the nuclear hormone receptor super family,
is a key molecular target in the etiology and progression of prostate
cancer.2–6 Binding of the endogenous AR ligand dihydrotestoster-
one stabilizes and protects the AR from rapid proteolytic degrada-
tion. The early stages of prostate cancer tumor growth are
androgen dependent and respond well to androgen ablation,2–6
either via surgical castration or by chemical castration with a
luteinizing hormone releasing hormone agonist in combination
with an AR antagonist, such as bicalutamide.
Although introduction of androgen deprivation therapy repre-
sented a major advance in prostate cancer treatment, recurrence
within 1–2 years typically marks transition to the so-called
castrate-resistant state, in which the tumor continues to grow in
the presence of low circulating endogenous ligand and is no longer
responsive to classical AR antagonists.2–6 Castrate-resistant
prostate cancer (CRPC) is a largely unmet medical need with a
5-year survival rate of less than 15%. Antimitotic agents docetaxel
and cabazitaxel, testosterone biosynthesis inhibitor abiraterone
acetate and second generation AR antagonist enzalutamide
(MDV3100) are the currently approved small-molecule drugs that
have been shown to provide survival benefit.7–10
Recent evidence from both pre-clinical and clinical studies is
consistent with the importance of re-activation of AR signaling in
a majority of castrate-resistant prostate tumors.2–6 It is also well
established that the functional AR in castrate-resistant tumors is
frequently mutated or amplified, and that over-expression can
convert hormone-responsive cell lines to hormone refractory.
Recent second-generation AR antagonists have been designed that
retain antagonism in over-expressing cell lines, and among these
agents enzalutamide11 has recently successfully met efficacy crite-
ria in a large Phase III clinical trial.12
By analogy with fulvestrant,13 an estrogen receptor (ER) down-
regulator approved by the FDA in 2002 for treatment of advanced
breast cancer and initially characterized as a pure ER antagonist, a
Y
N
X
R
N
N
N
N
N
N
N
N
N
N
1
2 X-Y = NCH2, N, CH,
N
F
F
CH(OH), CHO
F
F
F
F
⇑
Corresponding author. Tel.: +44 1625 515708; fax: +44 1625 510097.
E-mail address: rob.bradbury@astrazeneca.com (R.H. Bradbury).
Figure 1. Structures of lead AR downregulator 1 and chemotype 2.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.056

1946
R. H. Bradbury et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1945–1948
ligand which downregulates the AR represents one of a number of
potential approaches3–6 to treatment of CRPC via a sustained
reduction in tumor AR content. We recently described derivation
from a novel 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine
ligand of AR inhibitor 1 (Fig. 1).14 The compound also causes AR
downregulation15 and high plasma levels following oral adminis-
tration in pre-clinical models compensate for moderate cellular
potency.14,15
Although 1 showed excellent pharmacokinetic properties in rat
and dog and low turnover in isolated cryopreserved human hepa-
tocytes, two other properties of the compound precluded further
progression. Firstly, 1 was moderately potent in an IonWorks™
hERG assay16 (pIC50 5.65), implying that there was unlikely to be
sufficient margin between predicted efficacious human drug con-
centration and the concentration that could potentiate the hERG
ion channel and increase the risk of adverse cardiovascular events
in patients.17 Secondly, due to low equilibrium pH7.4 aqueous sol-
X
Cl
(a)
N
N
N
N
F
N
N
N
N
N
F
F
F
F
F
4a X = NCO2Bu-t
4b X = NH
3
(b)
(d)
N
(c)
R
X = NH
OH
X
N
N
R
N
N
N
N
N
N
N
N
F
F
5a R = 4-F
6a X = CH, R = F
6b X = N, R = H
F
F
F
5b R = 2,3-di-F
F
ubility (8 lM), the maximum absorbable dose (MAD) of 1 calcu-
lated using a gastrointestinal simulated model18 was significantly
lower than the predicted efficacious human dose derived from an
in-house physiologically-based pharmacokinetic (PBPK) model.19
To address these issues, we carried out a comprehensive medic-
inal chemistry lead optimisation programme20,21 centred around
chemotype 2, and in this publication we describe the key advances
that led to clinical candidate AZD3514 (12) that is being evaluated
in a Phase I clinical trial.22
Illustrative compounds selected from several hundred diverse
examples prepared during the course of this work are listed in Ta-
ble 1, and synthetic routes are outlined in Schemes 1–3.20,21 As part
of synthesis of wider compound libraries, benzyl piperazine deriv-
atives 5a–b and piperidinol derivatives 6a–b (Scheme 1) were
readily accessed from previously described precursors,14 reductive
amination of piperazine intermediate 4b with the appropriate fluo-
rinated aryl aldehyde giving 5a–b and displacement of chloro-
triazolopyridazine 3 with the appropriate aryl piperidinol23,24
giving 6a–b. Analogously to published work,25 the dihydro triazo-
lopyridazine intermediate 7 could be cleanly obtained by catalytic
hydrogenation of the corresponding N-protected precursor 4a un-
der atmospheric pressure at 50 °C followed by de-protection
(Scheme 2). Reductive amination with 4-fluorobenzaldehyde then
gave 8.
Scheme 1. Synthesis of compounds 5a–b, 6a–b. Reagents and conditions: (a) t-Butyl
piperazine-1-carboxylate, DIPEA, EtOH, 70 °C; (b) TFA, DCM, 20 °C; (c) 4-fluoro-
benzaldehyde or 2,3-difluorobenzaldehyde, (polystyrylmethyl)trimethylammoni-
um cyanoborohydride, AcOH, DCM, 20 °C; (d) 4-(4-fluorophenyl)piperidin-4-ol23 or
4-(pyridin-3-yl)piperidin-4-ol,24 DIPEA, DMF, 80 °C.
NH
N
N
N
(a), (b)
(c)
F
4a
N
F
N
F
N
N
N
N
N
N
F
F
7
F
8
F
Scheme 2. Synthesis of compound 8. Reagents and conditions: (a) H2, 5% Pd-C,
MeOH, 50 °C; (b) TFA, DCM, 20 °C; (c) 4-fluorobenzaldehyde, (polystyrylmethyl)-
trimethylammonium cyanoborohydride, AcOH, DCM, 20 °C.
appropriate piperidine26 (Scheme 3). Thus alkylation of 9a with
2-(1-methyl-1H-pyrazol-5-yl)ethanol27 gave 10 and alkylation of
9a–b with 2-(4-acetylpiperazine-1-yl)ethanol28 gave 11a–b. Cata-
lytic hydrogenation of 11a then provided 12.
Also as part of synthesis of wider libraries, compounds 10–12
containing a neutral or moderately basic side chain were prepared
by a route involving as the key step Mitsnobu reaction of the
Compounds listed in Table 1 were evaluated in a previously-de-
scribed AR downregulation assay14 that specifically quantifies
nuclear AR levels in human LNCaP prostate cancer cells in the ab-
sence of androgen. Also included in Table 1 are data from a number
phenol precursors 9a–b, readily obtained from
3 and the
Table 1
AR-mediated cellular downregulation,14 IonWorks™ activity,15 logD,29 aqueous solubility, rat and human protein binding, and human hepatocyte stability data for 1, 5a–b, 6a–b,
8, 10–12
a
b
c
Entry
AR downregulation pIC50
IonWorks™ pIC50
logD pH7.4
Solubility
l
M pH7.4
% Free rat/humand
Human hepatocyte Clinte l/min/106 cells)
(l
1
5.82
5.8
5.65
4.97
<4
4.74
4.02
4.53
4.75
4.95
<4
2.9
3.5
3.6
3.5
2.1
2.8
>4.3
3.2
2.2
2.5
8.4 (Cryst)
16 (Undefined)
NVf
<0.9 (Cryst)
100 (Cryst)
520 (Semicryst)
<0.73 (Cryst)
5.4 (Cryst)
9.2/4.4
3.4/2.0
1.8/1.7
3.6/4.0
34/26
<3
52
22
<3
<3
3.7
12
12
<3
<3
5a
5b
6a
6b
8
10
11a
11b
12
5.68
5.43
4.97
5.23
6.63
6.49
5.98
5.75
13/12
0.21/0.16
1.2/2.7
6.4/17
9.4/12
190 (Semicryst)
577 (Cryst)
<4
a
b
c
n P7, SEM values are available in the Supplementary data.
n P2.
24 h thermodynamic solubility of solid sample determined in 0.1 M phosphate buffer (parentheses refer to visual examination of physical form of undissolved sample
under a microscope at 24 h timepoint).
d
Determined from DMSO stock solution by equilibrium dialysis in 10% plasma from Alderley Park Han Wistar rats or 10% human plasma supplied by Quintiles.
e
Rate of metabolism determined from DMSO stock solution in isolated cryopreserved human hepatocytes diluted to 1 Â 106 cells/ml.
f
No value obtained.

R. H. Bradbury et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1945–1948
1947
OH
O
N
N
X
(a)
N
N
N
F
N
F
N
N
N
N
N
N
X = H
F
F
9a X = H
F
9b X = OH
F
10
(b)
O
O
N
N
X
N
N
O
N
O
(c)
N
N
N
N
N
N
N
N
N
X = H
F
F
11a X = H
F
F
F
F
12
11b X = OH
Scheme 3. Synthesis of compounds 10, 11a–b, 12. Reagents and conditions: (a) 2-(1-Methyl-1H-pyrazol-5-yl)ethanol,27 Ph3P, diisopropyl azodicarboxylate, THF, 20 °C;
(b) 2-(4-acetylpiperazine-1-yl)ethanol,28 Ph3P, diisopropyl azodicarboxylate, THF, 20 °C; (c) H2, 10% Pd-C, MeOH, 50 °C.
of routine in-house physical property, metabolic stability and
safety assays.
IonWorks™ assay. Binding of 12 to the AR was confirmed in ligand
displacement assays, the estimated Ki of 12 being 5 M in a fluo-
rescence polarisation assay using rat AR ligand binding domain30
l
To address the hERG activity of lead AR downregulator 1, we
considered a number of approaches reported in the medicinal
chemistry literature,16 including subtle structural effects, removal
of the basic piperazine nitrogen and reducing lipophilicity. Of a
wide range of aryl substituents investigated, replacement of the
4-cyano substituent by 4-fluoro (5a) maintained cellular potency
and reduced activity in the IonWorks™ assay. More notably, 2,3-
difluoro substitution (5b) obviated IonWorks™ activity (pIC50 <4)
while maintaining cellular potency. These compounds were not
progressed, however, as predicted efficacious human dose was sig-
nificantly increased over 1 due to inferior human hepatocyte
stability.
and 2.2 lM in a radiolabelled assay using full length AR derived
from LNCaP cell lysates.31,32
As representative of compounds with differing overall profile,
in vivo efficacy of compounds 6b, 10 and 12 was assessed in the
Hershberger assay,33 a longstanding model used in the discovery
of the AR antagonist bicalutamide,34 in which effects on accessory
sex organ weight in immature castrated rats stimulated with tes-
tosterone propionate serve as a marker for intervention via the
AR. Comparably to lead compound 1,14 compounds 6b, 10 and 12
dosed orally at 50–100 mg/kg twice daily in the Hershberger mod-
el for 7 days caused a significant inhibition of testosterone-induced
growth of rat seminal vesicles (data not shown), the magnitude of
effect being comparable to that seen with bicalutamide dosed at
2 mg/kg. Analysis of plasma samples 18 h subsequent to adminis-
tration of the final dose showed free concentrations comparable
to the IC50 for nuclear AR downregulation.
We were aware from earlier work14 that removal of the basic
piperazine nitrogen increased lipophilicity and compromised
physical properties. By way of compensation, the corresponding
aryl piperidinols were prepared (e.g., 6a). For this sub-series of
compounds, acceptable overall properties could only be achieved
through replacement of the aryl ring with a heteroaryl moiety,
for example 6b, for which increased rat and human free fraction
arguably compensate for reduced cellular potency. Partial reduc-
tion of the triazolopyridazine ring surprisingly gave a significant
reduction in lipophilicity, with consequent improvement in overall
compound profile (hERG, physical properties, human hepatocyte
stability, e.g., compare 8 with 5a).
For input into our in-house PBPK model, low dose rat and dog
blood pharmacokinetic parameters were generated on compounds
6b, 10 and 12 (Table 2), and MAD values were predicted using gas-
trointestinal simulated modelling.18 In summary, developability
risks for less potent but soluble compound 6b and for more potent
Examination of the previously proposed14 binding mode for the
triazolopyridazine ligand to the AR suggested an alternative way to
improve physical properties of compounds lacking the basic piper-
azine nitrogen, through incorporation of a solubilising end group
attached via a linker to the 3- or 4-position of the aryl ring. Of a
wide range of linkers and end groups investigated by parallel syn-
thesis, polar and weak to moderately basic heterocycles attached
via a 4-alkoxy linker emerged as of particular interest (e.g., 10
and 11a), in that cellular potency and in vitro hERG margin were
significantly improved over lead compound 1.
As described earlier, the low aqueous solubility and free fraction
of compounds such as 11a was significantly improved by prepara-
tion of the corresponding piperidinol (11b) and dihydro triazolopy-
ridazine (12). These compounds also showed low human
hepatocyte turnover and no detectable activity in the hERG
Table 2
Rata and dogb pharmacokinetic parameters for 6b, 10, 12
Entry
Species
Vdss l/kg
Cl ml/min/kg
Bioavailability (%)
6b
Ratc
5.7
1.3
38
18
>75
>75
Dogd
10
12
Rate
2.3
2.7
22
9.2
43
18
Dogd
Ratf
2.1
3.2
6.6
12
74
>75
Dogd
a
b
c
d
e
f
Mean blood PK parameters from 2 male Alderley Park Han Wistar rats.
Mean blood PK parameters from 1 male zand 1 female Alderley Park beagle.
Dosed at 20 lmol/kg iv and 50 lmol/kg po.
Dosed at 2
Dosed at 3
Dosed at 4
lmol/kg iv and 10
lmol/kg po.
l
l
mol/kg iv and 10
mol/kg iv and 5 lmol/kg po.
l
mol/kg po.

1948
R. H. Bradbury et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1945–1948
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but less soluble compound 10 centred around high predicted dose
and low MAD, respectively, whereas for compound 12 with the
best overall property profile MAD significantly exceeded a pre-
dicted efficacious human dose in the low hundreds of milligrams
twice daily.
Compound 12, designated AZD3514, was chosen as clinical can-
didate and is being evaluated in a Phase I trial in patients with
CRPC.22 Detailed biological characterisation of compound 12,
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