Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.04.024

The orally-active CYP17A1 inhibitor abiraterone acetate (AA) decreases adrenal and intratumoral androgen biosynthesis and is an effective agent for the treatment of prostate cancer. Abiraterone potently inhibits both reactions catalyzed by CYP17, the 17α-hydroxylase (hydroxylase) reaction as well as the 17,20-lyase (lyase) transformation. CYP17 hydroxylase inhibition prevents the synthesis of adrenal glucocorticoids and causes an accumulation of circulating mineralocorticoids. As a consequence of potent CYP17 hydroxylase inhibition (i.e., lack of lyase selectivity), AA must be co-administered with the cortisol replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome (MES). Herein, we describe rationally-designed, CYP17 lyase-selective inhibitors that could prove safer and more effective than abiraterone. Using proprietary methodology, the high-affinity pyridine or imidazole metal-binding group found in current clinical CYP17 inhibitors was replaced with novel, less avid, metal-binding groups in concert with potency-enhancing molecular scaffold modifications. This process produced a unique series of CYP17 lyase-selective inhibitors that included the oral agent 6 (VT-464), now in Phase 2 prostate cancer clinical trials. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases.

Full text of DOI:10.1016/j.bmcl.2014.04.024

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2444–2447
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase
inhibitors
⇑
Stephen W. Rafferty, Joel R. Eisner, William R. Moore, Robert J. Schotzinger, William J. Hoekstra
Viamet Pharmaceuticals, Inc., Durham, NC 27703, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The orally-active CYP17A1 inhibitor abiraterone acetate (AA) decreases adrenal and intratumoral andro-
gen biosynthesis and is an effective agent for the treatment of prostate cancer. Abiraterone potently
inhibits both reactions catalyzed by CYP17, the 17a-hydroxylase (hydroxylase) reaction as well as the
Received 13 March 2014
Revised 3 April 2014
Accepted 7 April 2014
Available online 16 April 2014
17,20-lyase (lyase) transformation. CYP17 hydroxylase inhibition prevents the synthesis of adrenal glu-
cocorticoids and causes an accumulation of circulating mineralocorticoids. As a consequence of potent
CYP17 hydroxylase inhibition (i.e., lack of lyase selectivity), AA must be co-administered with the cortisol
replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome
(MES). Herein, we describe rationally-designed, CYP17 lyase-selective inhibitors that could prove safer
and more effective than abiraterone. Using proprietary methodology, the high-affinity pyridine or
imidazole metal-binding group found in current clinical CYP17 inhibitors was replaced with novel, less
avid, metal-binding groups in concert with potency-enhancing molecular scaffold modifications. This
process produced a unique series of CYP17 lyase-selective inhibitors that included the oral agent 6
(VT-464), now in Phase 2 prostate cancer clinical trials. The chemical methodology described is poten-
tially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad
array of diseases.
Keywords:
CYP17 lyase
Prostate cancer
Ó 2014 Elsevier Ltd. All rights reserved.
Cytochrome P-450 enzymes (CYPs), due to high homology
inclusive of a common heme–iron motif, present a major challenge
to the discovery of target-selective inhibitors. The potent CYP17
inhibitor, abiraterone acetate, inhibits cortisol biosynthesis and
produces side-effects associated with MES at effective doses.1
Our metalloenzyme inhibitor design strategy, which focuses on
the metal-binding group (MBG), has produced some of the most
alternative MBGs2 [e.g., less basic 4-(1,2,3-triazole)] was followed
by further scaffold optimization of the naphthyl-triazolyl-butanol
inhibitor series 3 as described below.
Many metalloenzyme inhibitors consist of two chemical com-
ponents: the MBG, the portion of the inhibitor designed to bind
to the metal, and the scaffold, the portion of the inhibitor recog-
nized by the amino acid residues that form the substrate-binding
site of the metalloenzyme. The MGB is often a major contributor
to the overall potency of the inhibitor (though it is acknowledged
that many examples of metalloenzyme inhibitors have been
reported that do not utilize a MBG). The attraction of the MBG to
the metal ion is governed by electronic factors. The metal ion is
generally electron-deficient, while the MBG is nucleophilic. The
magnitude of the MBG’s interaction with the metal, and therefore
inhibitor potency, can be ‘tuned’ by modulating its electronic char-
acter. If the metal/MBG interaction is strong the inhibitor will cer-
tainly be effective against the intended target but may also inhibit
unintended related metalloenzymes. Our approach has been to
attenuate the magnitude of the MGB/metal interaction in order
to initially improve target selectivity while retaining residual
potency. Inhibitor potency and selectivity are then further
improved through modifications to the scaffold that increase the
magnitude of interactions within the substrate binding pocket.
selective CYP172,3 and fungal CYP51A1 (lanosterol 14
a-demethyl-
ase)4 inhibitors reported for the potential treatment of prostate
cancer and fungal infections, respectively. This iterative technology
approach synergistically combines the application of inorganic
chemistry with classical medicinal chemistry (i.e., in silico-derived
MBGs are affixed to progressable chemical scaffolds). The process
is exemplified in Scheme 1 wherein starting point 1 is a reported
potent inhibitor of rat CYP17 lyase (IC50 = 0.029
lase (IC50 = 0.14 M) as well as the human enzyme (IC50s are 0.05
and 0.22
M for lyase and hydroxylase activities, respectively).5
lM) and hydroxy-
l
l
Given its potency, lyase selectivity, and physicochemical proper-
ties, imidazole 1 was chosen as a non-steroidal starting point to
more lyase-selective CYP17 inhibitors.
A survey of potential
⇑
Corresponding author. Tel.: +1 919 467 8539x303.
E-mail address: whoekstra@viamet.com (W. J. Hoekstra).
http://dx.doi.org/10.1016/j.bmcl.2014.04.024
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

S. W. Rafferty et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2444–2447
2445
HO
HO
HO
O
O
N
O
O
N
MBG
R
N
N
H
N
H
1
2
3
Scheme 1.
MBGs were initially selected using an in silico method that rank
ordered them by affinity for heme–iron. Emphasis was placed on
MBGs with lower affinity than the current high-potency imidazoles
and pyridines that appear in inhibitors that respectively show
modest (TAK-700) or no selectivity (abiraterone) for CYP17 lyase
compared to hydroxylase. Due to lack of lyase selectivity, these
inhibitors must be administered with prednisone to address
MES-associated side-effects (hyperkalemia, hypertension).1
CYP17, a steroidogenic enzyme that is required for androgen
biosynthesis, catalyzes two sequential chemical steps. CYP17
hydroxylase catalyzes the conversion of progesterone and preg-
nenolone to their 17-hydroxy analogs and is required for the syn-
thesis of glucocorticoids (Fig. 1).6 CYP17 lyase breaks the covalent
bond between C17 and C20 of 17-hydroxypregnenolone, forming
the androgen, dehydroepiandrosterone (DHEA), and thus repre-
sents the first committed step in sex steroid biosynthesis. Though
inhibition of either CYP17 hydroxylase or lyase should result in
decreased androgen biosynthesis, lyase is the preferred point of
intervention since hydroxylase inhibition also prevents glucocorti-
coid synthesis and causes the accumulation of mineralocorticoids.
Since cortisol is the most abundant steroid synthesized and
secreted by the adrenal gland, mineralocorticoids get pulled by
mass action into the glucocorticoid pathway and will unlikely
accumulate as a result of CYP17 lyase-selective inhibition.7
A key challenge to the design of lyase-selective inhibitors is that
the single-chain CYP17 protein uses the same active site to cata-
lyze both the lyase and hydroxylase reactions.8 Both reactions
require heme–iron and oxidoreductase cofactors, as well as NADPH
and molecular oxygen as co-substrates. However, CYP17 has an
additional cofactor, cytochrome b5, that enhances lyase activity.9
The crystal structure of the CYP17 hydroxylase conformation has
been solved but not the CYP17-cytochrome b5 complex.10 Thus,
there is little structural information to guide the design of CYP17
lyase-selective inhibitors and their optimization has been
empirical to date. Not surprisingly, given the dearth of structural
information and protein target similarity constraints, all CYP17
inhibitors reported to date affect both the hydroxylase and lyase
enzyme functions to some extent. Our design and discovery strat-
egy focused on the investigation of alternative, lower-affinity
MBGs on the premise that lyase-selective CYP17 inhibitors may
provide safer and more effective clinical agents. Herein, we dis-
close a unique series of inhibitors, including the Phase 2 clinical
agent 6 (VT-464), which exhibit selective potency for CYP17 lyase.
Compounds 2a–2i are representatives of an array of MBG tar-
gets (2, Scheme 1) related to imidazole standard 15 that were syn-
thesized and initially tested in a rat CYP17 lyase screening assay
(Table 1).11 The inhibitors were synthesized as racemates by cou-
pling of 6,7-dimethoxy-naphthalene-2-isopropyl ketone with the
requisite lithiated heterocycle in modest yields (15–65%;
Scheme 2).12,13 Heteroaromatic MBGs were selected that encom-
passed a wide range of basicities though emphasis was placed on
low-affinity moieties that might demonstrate selectivity for rat
CYP17 lyase versus the metabolic human enzyme CYP3A4.14 As
shown in Table 1, the oxazole 2f and 4-pyridine 2h furnished ade-
quate lyase potency (IC50s of 86 and 60 nM) but both inhibited
CYP3A4 as well (IC50s <10
lM). An MBG that exhibited threshold
potency (IC50 = 0.18 M) and markedly enhanced selectivity over
l
CYP3A4 (317-fold) was the 4-(1,2,3-triazole) 2c. This promising
MBG was selected for further optimization within the naphthalene
chemical series.
Triazole 2c exhibited equal potency for rat and human CYP17
lyase (IC50 = 0.18
through scaffold modifications to achieve the following thresholds:
h-CYP17 lyase potency IC50 <0.2 M, h-CYP17 lyase/hydroxylase
lM) and was selected for further optimization
l
selectivity >10-fold, and selectivity >50-fold for h-CYP17 lyase
versus h-CYP3A4. Representative 4-(1,2,3-triazoles) 3a–f contain-
ing a variety of substituents (R) at the 6- and 7-positions were
synthesized and tested for human lyase, human hydroxylase, and
CYP3A4 potency in comparison to imidazole 1 (Table 2).12 Several
molecules in this chemical series (2c, 3b, 3c) exhibited improved
lyase selectivity versus hydroxylase and CYP3A4 (H/L and 3A4/L
Table 1
In vitro activity of naphthalene-based CYP17 inhibitors
HO
O
MBG
O
a,11
b,11
No.
MBG
Rat CYP17 lyase IC50
h-CYP3A4 IC50
2a
2b
2c
2d
2e
2f
3-Pyrazole
4-Pyrazole
4-(1,2,3-Triazole)
3-(1,2,4-Triazole)
5-Thiazole
5-Oxazole
3-Pyridine
4-Pyridine
4-Pyrimidine
4-Imidazole
1.6
1.8
27
57
100
0.77
6.5
9.4
4.5
18
0.43
0.18
7.1
0.29
0.086
4.2
0.060
0.44
0.029
2g
2h
2i
15
1.6
a
IC50
IC50
(
l
M) measured in a rat testicular microsome preparation.
M) measured in a pooled human hepatocyte microsome preparation.
b
(l
Figure 1. Human adrenal steroid biosynthetic pathway.

2446
S. W. Rafferty et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2444–2447
N
N
O
HO
N
O
O
O
O
O
O
N
i-PrCOCl
AlCl3
1) n-BuLi/
SEM
N
N
H
2) (n-Bu)4NF/CsF
4
5
2c
Scheme 2.
Table 2
In vitro CYP potency and selectivity of triazolyl naphthalene-based CYP17 inhibitors
HO
N
N
R
N
H
3a-f
h-H/L ratiob
h-CYP3A4
IC50
3A4/L ratio
a
a,11
No.
R
h-Lyase IC50
h-Hydroxylase IC50
c
2c
3a
3b
3c
3d
3e
3f
1
6,7-Di-OMe
6,7-Di-OCHF2
6,7-Di-OCH2CF3
6-(5-oxazole)
6-OCHF2
6-OCH2CF3
6-(2-Thiophene)
—
0.18
0.17
0.31
0.94
0.33
0.57
>4
2.3
0.69
3.7
13
0.074
1.0
13
3.9
12
57
23
25
320
140
80
110
42
P340
<20
32
14
102
14
P195
81
0.22
1.8
<3.0
4.4
12
0.22
0.05
1.6
a
b
c
IC50 (lM) measured in a recombinant human enzyme yeast microsome system.
Human IC50 ratio as an indicator of lyase selectivity; H = hydroxylase, L = lyase.
Assay described in Table 1.
N
N
N
F
F
F
F
F
F
F
F
O
O
HO
O
O
O
O
O
O
N
1) BBr3/DCM
1) t-BuLi/
SEM
N
N
H
2) BrF2CCO2Et/
K2CO3
2) TBAF/CsF
3) Chiral HPLC
6
5
7
Scheme 3.
ratios, Table 2) compared to the literature 1-imidazole (1). While
2c exhibited good lyase potency and promising selectivity it was
not evaluated further due to poor human liver microsome stability
(29% parent 2c remaining after 60 min compared to 54% remaining
for 3a).
Racemic compound 3a, an analogue of 2c, furnished superior
lyase potency and selectivity. Though the active enantiomer of
3b also exhibited excellent selectivity, it furnished inferior lyase
potency compared to racemic 3a (3b enantiomer IC50 data not
shown). The enantiomers of 3a were synthesized and isolated
Table 3
In vitro potency, selectivity, and oral activity of 3 classes of CYP17 inhibitors
N
F
F
HO
O
O
N
N
N
H
AcO
F
F
6
Abiraterone Acetate (AA)
a
a
No.
h-Lyase IC50
h-Hydroxylase IC50
h-H/L ratio
Mean testosterone SEb (ng/mL)
Mean progesterone SEb (ng/mL)
6
0.069
0.05
0.015
0.670
0.22
0.0025
9.7
4.4
0.17
0.37 0.02*
0.30 0.0d,*
0.30 0.0d,*
1.2 0.1
1c
AA
3.9 0.9*
2.1 0.3d,*
a
b
c
Method described in Table 2.
Plasma steroid values measured by LC/MS/MS 2 h post-dose.
Racemate 1 was used for h-lyase and hydroxylase IC50 determinations and administration to hamsters.
All values at or below the LLOQ of 0.3 ng/mL.
d
*
p 60.05 versus 2 h vehicle control values of 1.98 0.057 ng/mL for testosterone and 1.02 0.05 ng/mL for progesterone.

S. W. Rafferty et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2444–2447
2447
according to Scheme 3.12 Briefly, 6,7-dimethoxy-naphthyl-isopro-
pyl ketone 5 was demethylated under strongly-acidic conditions
(boron tribromide) and the resultant o-dihydroxy-naphthalene
intermediate then capped with two difluoromethyl groups using
6. Conley, A. J.; Bird, I. M. Biol. Reprod. 1997, 56, 789.
7. Geller, D. H.; Auchus, R. J.; Miller, W. L. Mol. Endocrinol. 1999, 13, 167.
8. Miller, W. L. J. Clin. Endocrinol. Metab. 2012, 97, 59.
9. Auchus, R. J.; Lee, T. C.; Miller, W. L. J. Biol. Chem. 1998, 273, 3158.
10. DeVore, N. M.; Scott, E. E. Nature 2012, 482, 116.
11. IC50 values for inhibition of rat or human CYP enzymes were determined using
microsomal enzyme preparations, an NADPH-regenerating system (Sigma–
standard base-mediated
a-bromo-difluoroacetate conditions to
furnish intermediate 7. Ketone 7 was then converted to 3a by
sequential addition of lithiated 1-N-SEM-triazole and subsequent
SEM removal with fluoride. Resolution of the antipodes of 3a using
chiral HPLC provided a potent CYP17 lyase inhibitor 615 that dem-
onstrated both exceptional in vitro lyase/hydroxylase selectivity
(ꢀ10-fold)2,3 and oral activity in a hamster model of androgen bio-
synthesis inhibition (Table 3).16,17
Aldrich, St. Louis, MO), and substrate concentrations of 1
pregnenolone for lyase and 150 testosterone (experimental Km) for
CYP3A4. Reactions were analyzed for product using HPLC/MS/MS methods,
and IC50 values (in M) were determined from a 4-parameter logistical fit to
lM 17a-hydroxy-
lM
l
the dose response data (K. Lewis, OpAns, LLC, Durham, NC).
12. Hoekstra, W.J.; Schotzinger, R.J.; Rafferty, S.W. U.S. Patent 8,389,543, 2013.
13. Matsunaga, N.; Kaku, T.; Ojida, A.; Tasaka, A. Tetrahederon: Asymmetry. 2004,
15, 2021.
14. Using spartan 2006 program package, Me-metal binding group (Me-MBG)
ligands were minimized using the MMFF-94 force field and optimized with the
semi-empirical PM3 method. The CYP-51 Fe-porphyrin construct (Podust,
PNAS, 2001, 98, 3068) was minimized (MMFF94) and then optimized using the
PM3 semi-empirical method to obtain unligated structure. Me-MBGs were
introduced and the energy was determined by a single point calculation. The
Fe-porphyrin and Me-MBGs were complexed with only the Me-MBG ligand
free to move during optimization. Next, Me-MBGs were submitted for
geometry optimization and enthalpies measured (K. Page and W. Mascarella,
Research Triangle Institute).
Inhibitor 6 and the comparator compounds abiraterone acetate
(AA), an approved CYP17 inhibitor,1 and the active imidazole 1,5
were evaluated for their effects on steroid biosynthesis in hamster
following
a
single 50 mg/kg oral dose.16,17 All three CYP17
inhibitors significantly decreased plasma testosterone concentra-
tions to the lower limit of quantitation (LLOQ) 2 h post-dose
(Table 3). However, administration of the 3-pyridine, AA, and the
imidazole 1 produced a statistically-significant increase in plasma
progesterone, a marker for CYP17 hydroxylase inhibition. In con-
trast, triazole 6 administration produced only a modest increase
in progesterone consistent with its superior in vitro CYP17 lyase/
hydroylase selectivity. Similar in vivo effects on testosterone and
progesterone following oral administration of 6 and AA were
observed in castrate monkeys.3
In summary, we have described the design, synthesis, and dis-
covery of novel 4-(1,2,3-triazole)-based CYP17 lyase-selective
inhibitors. An orally active representative from this chemical series,
VT-464 (6), is in clinical development for the treatment of patients
with castration-refractory prostate cancer. The MBG-based design
process described herein was used to produce the most lyase-selec-
tive CYP17 inhibitors reported to date, including the potent oral
clinical agent 6. The process is generalizable and broadly applicable
to the design and evaluation of new and improved chemical entities
within the metalloenzyme inhibitor class.
15. Compound 6 was synthesized from 5 as follows: To a stirred solution of 5 (18 g,
69 mmol) in DCM (180 mL) was added BBr3 (87.2 g, 348 mmol) dropwise at
À40 °C. After completion of addition, stirring was continued for 1 h at À40 °C
and 1 h at RT. The reaction mixture was poured into ice-cold water and the
aqueous layer then extracted with DCM (2 Â 200 mL). The combined organic
extracts were washed with water (100 mL), brine (100 mL), and dried
(Na2SO4). After filtration and solvent evaporation in vacuo, the crude
material was purified by column chromatography (SiO2, 100–200 mesh) to
afford the catechol intermediate (9.0 g, 39 mmol, 56%) as a brown solid. To a
stirred solution of this intermediate (5.0 g, 21.7 mmol) in DMF (50 mL) were
added ethyl bromodifluoroacetate (17.6 g, 86.6 mmol) and K2CO3 (18 g,
130 mmol), and the mixture was stirred at 110 °C for 48 h. The reaction
mixture was poured into cold water and the aqueous layer then extracted with
DCM (2 Â 100 mL). Combined organic extracts were washed with water
(50 mL), brine (50 mL), and dried (Na2SO4). After filtration and evaporation
of solvent, the crude material was purified by column chromatography (SiO2,
100–200 mesh) to afford solid 7 (2.3 g, 4.3 mmol, 32%). To a stirred solution of
1-N-SEM-1,2,3-triazole (2.25 g, 11.8 mmol) in dry Et2O (25 mL) was added t-
BuLi (0.69 g, 10.7 mmol) dropwise at À78 °C under inert atmosphere. After
stirring for 1 h at À78 °C, 7 (1.5 g, 2.83 mmol) in dry ether (25 mL) was added
to reaction mixture and stirring continued for 1 h at À78 °C. The reaction
mixture was quenched with sat’d NH4Cl solution and extracted with EtOAc
(2 Â 50 mL). Combined organic phases were washed with brine, dried
(Na2SO4), and concentrated to afford the SEM-protected precursor of 3a
(2.0 g) as a syrup. Crude material was taken to the next step without further
purification. To a stirred solution of this material (3.0 g, 5.6 mmol) in THF
(30 mL) were added TBAF (1.48 g, 5.67 mmol, 1 M in THF) and CsF (2.58 g,
16.8 mmol) at RT. The reaction mixture was stirred at 80 °C for 4 h. The
mixture was concentrated in vacuo; the obtained residue was partitioned
between water and DCM. The organic phase was separated and the aqueous
layer was extracted with DCM (2 Â 25 mL); the combined organic phases were
washed with brine, dried (Na2SO4) and concentrated to give crude material.
The crude material was purified by column chromatography (SiO2, 100–200
mesh) to afford 3a (2.2 g, 5.5 mmol, 61%) as a white solid. 1H NMR (500 MHz,
CDCl3): d 11.4 (br s, 1H), 8.03 (s, 1 H), 7.76–7.61 (m, 5H), 6.60 (t, JF,H = 74 Hz,
2H). 2.88 (br s, 1H), 2.86–2.80 (m, 1H), 0.97 (d, J = 7.0 Hz, 3H), 0.80 (d,
J = 7.0 Hz, 3 H). HPLC: 96%. MS (ESI): m/z 398 [M+H]+. Compound 6 was
isolated from racemate 3a using the following conditions: Column: Chiralpak
IC, 250 Â 4.6 mm, 5-micron; mobile phase: Isocratic n-hexane/IPA (95:5); Flow
rate: 1.00 mL/min; HPLC: 99.5% (13 mg isolated as a white powder); optical
Acknowledgments
We thank Dr. Richard Auchus for kindly providing recombinant
human CYP17 and cytochrome b5 preparations, and Drs. Barry
Sharpless and Manuel Navia for their insightful inhibitor design
guidance.
References and notes
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rotation [
a]D: À54° (c = 0.5 % in MeOH).
16. Hamsters were chosen as a model species because they, unlike most rodents,
have adrenal CYP17 similar to human Conley, A. J.; Bird, I. M. Biol. Reprod. 1997,
56, 789.
Phase
1 Multiple-Ascending-Dose Trial of VT-1161, a Highly Potent and
17. Gonadally-intact, experimentally-naïve male hamsters (6 per group) were
administered a CYP17 inhibitor (50 mg/kg by oral gavage in 20% cremaphor) at
the same morning time and then blood samples were collected for the
determination of plasma steroid concentrations 2 h later.
Selective Oral Antifungal Agent for the Treatment of Superficial Fungal
Infections’. Abstract #7516, Am. Acad. Dermatology Summer Academy
Meeting, 2013.
5. Matsunaga, N.; Kaku, T.; Ojida, A.; Tanaka, T.; Hara, T.; Yamaoka, M.; Kusaka,
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