Design and optimization of highly-selective fungal CYP51 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.05.068

While the orally-active azoles such as voriconazole and itraconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, li

Full text of DOI:10.1016/j.bmcl.2014.05.068

Accepted Manuscript
Design and Optimization of Highly-Selective Fungal CYP51 Inhibitors
William J. Hoekstra, Edward P. Garvey, William R. Moore, Stephen W.
Rafferty, Christopher M. Yates, Robert J. Schotzinger
PII:
S0960-894X(14)00577-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.05.068
BMCL 21682
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 April 2014
19 May 2014
20 May 2014
Please cite this article as: Hoekstra, W.J., Garvey, E.P., Moore, W.R., Rafferty, S.W., Yates, C.M., Schotzinger,
R.J., Design and Optimization of Highly-Selective Fungal CYP51 Inhibitors, Bioorganic & Medicinal Chemistry
Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.05.068
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Design and Optimization of Highly-Selective Fungal CYP51 Inhibitors
William J. Hoekstra*, Edward P. Garvey, William R. Moore, Stephen W. Rafferty,
Christopher M. Yates, and Robert J. Schotzinger
Viamet Pharmaceuticals Inc., Durham, NC 27703, USA
Abstract: While the orally-active azoles such as voriconazole and itraconazole are effective antifungal agents,
they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various
safety issues (e.g., drug-drug interactions, liver toxicity). Herein, we describe rationally-designed, broad-
spectrum antifungal agents that are more selective for the target fungal enzyme, CYP51, than related human
CYP enzymes such as CYP3A4. Using proprietary methodology, the triazole metal-binding group found in
current clinical agents was replaced with novel, less avid metal-binding groups in concert with potency-
enhancing molecular scaffold modifications. This process produced a unique series of fungal CYP51-selective
inhibitors that included the oral antifungal 7d (VT-1161), now in Phase 2 clinical trials. This series exhibits
excellent potency against key yeast and dermatophyte strains. The chemical methodology described is
potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad
array of diseases.
Cytochrome P450 enzymes (CYPs), due to high homology inclusive of a common heme-iron motif,
present a major challenge to the discovery of target-selective inhibitors. Many metalloenzyme inhibitors
consist of two chemical components: the metal-binding group (MBG), the portion of the inhibitor designed to
bind to the metal, and the scaffold, the portion of the inhibitor recognized by the amino acid residues that form
the substrate-binding site of the metalloenzyme. The MBG is often a major contributor to the overall potency
of the inhibitor, though 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 magnitude of the MBG’s interaction with
the metal, and therefore inhibitor potency, can be “tuned” by modulating its electronic character. If the
metal/MBG interaction is strong, potent inhibition of the target enzyme may be achieved but unintended
related metalloenzymes can be inhibited as well.
Scheme 1
Voriconazole
1
2
7
_______
* Corresponding author. Tel: 919-467-8539, ext. 303; email: whoekstra@viamet.com

The azole class of antifungal drugs inhibits fungal CYP51 (lanosterol demethylase) activity through
competitive, reversible binding to the heme cofactor located in the enzyme active site.1 Historically, there has
been relatively little variation in CYP51 inhibitor MBGs. First-generation antifungal drugs, such as
miconazole and ketoconazole, utilized the 1-imidazole MBG, a high-affinity ligand for heme-iron (e.g., 1d;
Table 1). These drugs also inhibited off-target human hepatic CYP enzymes leading to severe and sometimes
fatal liver problems.2 Second-generation azole antifungal drugs (e.g. itraconazole, voriconazole) utilized a 1-
(1,2,4-triazole) MBG. Compared to 1-imidazole, the triazole was a lower-affinity ligand for heme-iron and
this MBG alternative led to improved tolerability, but liver toxicity and drug-drug interactions remained
problematic.3 Our strategy to discover new, more selective agents focused on alternative, low-affinity MBGs.
Herein, we disclose a potent, selective series of inhibitors, including the Phase 2 antifungal clinical agent 7d
(VT-1161; Scheme 1, Table 3).4
We hypothesized that the MBG found in the azole class of drugs (e.g., voriconazole, itraconazole), the 1-
(1,2,4-triazole), is too high in heme-iron affinity and may be the source of CYP non-selectivity. Our approach
was to attenuate the magnitude of the MBG/metal interaction in order to improve target selectivity, likely at
the initial expense of overall CYP51 affinity. Inhibitor potency was to be improved through modifications to
the scaffold, thus increasing the magnitude of binding affinity within the substrate binding pocket rather than
via the metal interaction.
Table 1. Antifungal Activity and CYP3A4 Potency of Pyrimidines.
1
Compound
1a
b
MBG
C. albicans MICa
CYP3A4 IC50
1-(1,2,3-triazole)
1-tetrazole
>16
1
8.0
32
51
0.8
46
13
1b
1c
4-(1,2,4-triazole)
1-imidazole
2-tetrazole
>16
0.5
8
1d
1e
Voriconazole
1-(1,2,4-triazole)
0.06
a. Minimum concentration that achieved 50% inhibition of fungal growth; MIC units in µg/mL.5 b. Inhibition
of CYP3A4 measured in microsomes obtained from pooled human hepatocytes; IC50 units in µM.8
In order to investigate our hypothesis, we used a process which combined the application of inorganic
chemistry with classical medicinal chemistry. MBGs were initially selected using an in silico method that
rank-ordered them by their predicted affinity for heme-iron. The approach is exemplified in Scheme 1 wherein
voriconazole (1a) was chosen as a starting point, given its good potency (C. albicans MIC = 0.06 ug/mL)5 and

physicochemical properties,6 as well as its lower affinity for the anti-target, CYP3A4, than itraconazole
(CYP3A4 IC50 = 0.07 uM) or posaconazole (CYP3A4 IC50 = 0.05 uM). A survey of potential alternative
lower affinity MBGs, screened in silico,7 led to discovery of the active, low basicity 1-tetrazole 1b (Table 1).
Compounds 1a-1e are representatives from an array that was synthesized and then tested to assess in
vitro potency in fungal growth5 and CYP3A4 enzyme8 assays (Table 1). The yeast, C. albicans, was chosen
for initial antifungal testing because it is the species that most frequently causes invasive human infections.9
CYP3A4 was selected as the representative anti-target due to its prominent role in liver metabolism, and its
inhibition by the azole antifungals is a recognized source of numerous drug-drug interactions.10 The target
molecules were synthesized in modest yields (10-40%) as mixtures of the indicated enantiomeric pairs by
coupling the requisite azole-methyl 2,4-difluorophenyl ketone intermediate with LDA-treated 4-ethyl-5-
fluoro-pyrimidine.6 Heteroaromatic MBGs were selected to capture a range of basicities and the focus was
placed on low-affinity moieties that could be further optimized with scaffold modifications to realize both
antifungal potency (C. albicans MIC <1 µg/mL initially) and CYP selectivity targets (CYP3A4 IC50 > 50
µM). Analogues with promising C. albicans activity in the 0.5-1 µg/mL range from the array were 1-tetrazole
1b and 1-imidazole 1d. The 1-imidazole was not pursued further given its marked basicity (pKa = 6.8) and
pronounced CYP3A4 inhibition (IC50 = 0.8 µM). Though 1a-1e did not attain the initial 50-fold selectivity
goal, analogue 1b, encouragingly inhibited CYP3A4 activity weakly (IC50 = 32 µM). It was selected for
further exploration due to the low-basicity (and predicted iron affinity) of the 1-tetrazole MBG [basic pKa = -
1.1 vs. 2.3 for the potent standard 1-(1,2,4-triazole)].7
Figure 1. CYP51 active site view of (R)-(+)-2d docked into a C. albicans-CYP51 homology model.

Homology model dockings of 1b utilizing a C. albicans-CYP51 construct indicated that a potential
interaction could be facilitated with the conserved tyrosine-118 residue by incorporation of an aromatic group
vicinal to the N-1 position of the pyrimidine moiety (Fig. 1).11 A π-stacking interaction between a lipophilic,
aromatic replacement for the pyrimidine and the Tyr-118 was proposed.
Scheme 2
Thus, a representative series of 1-tetrazoles 2a-2f containing an electron-deficient 2,5-disubstituted
pyridine capable of interacting with Tyr-118, connected through a metabolically-resistant, electron-
withdrawing difluoromethyl linker,12 were synthesized and tested (Scheme 2, Table 2). Small substituents at
the 5-position of the pyridine (e.g., 2a-b; prepared from 5-H or 5-Cl analogues of 3) gave modest yeast
potency improvement compared to pyrimidine 1b while relatively large substituents provided significant yeast
potency increases (2d-f); substitutions at the 5-position of the pyridine had only a small effect on CYP3A4
potency (Table 2). Several molecules in this chemical series exhibited robust oral efficacy in a mouse model13
of invasive candidiasis (2a, 2b, 2d, 2e), indicative of both adequate plasma exposure and sustained metabolic
stability. Monocyclic and bicyclic heteroaromatic alternatives to pyridine were not pursued due to poor in vivo
efficacy (data not shown).14
Further examination of the homology model around the meta/para position of biaryls 2d-2f indicated
that potency could be further improved through an additional H-bonding interaction with Ser-378 in this
binding pocket region (e.g., with an ether moiety).15 The trifluoromethyl ether 7c and trifluoroethyl ether 7d
were synthesized as racemates, and following resolution of the single isomers,15-17 furnished highly-potent
growth inhibitors of representative yeast (C. albicans) and dermatophyte (T. rubrum) isolates (Table 3).

Table 2. In Vitro Potency and Oral Antifungal Activity of Difluoromethyl-Pyridines.
F
F
HO
N
N
N
N
F
N
R
F
2
b
C. albicans MICa
CYP3A4 IC50
Mouse Efficacyc
93%
Compound
1b
R
-
1
32
136
74
2a
2b
2c
2d
2e
2f
H
98%
0.25
Cl
100%
0.25
OCH2CF3
4-F-Ph
81%
0.06
72
99% d
0.016
<0.016
<0.016
53
4-CN-Ph
4-CF3-Ph
100%
16
94%e
>60
a. Minimum concentration that achieved 50% inhibition of fungal growth; MIC units in µg/mL.5 b. Inhibition
of CYP3A4 measured in microsomes obtained from pooled human hepatocytes; IC50 units in µM.8 c. Percent
reduction in kidney fungal burden13 following an oral dose of 50 mg/kg of 2a-c, 2e. All values were
significantly different than vehicle-treated controls (P <0.01), except for 2c. d. Oral dose of 10 mg/kg. e. Oral
dose of 20 mg/kg.
While other variably-substituted phenyl and pyridine analogues at the carbinol center were prepared and
tested (e.g., the racemic 2-F-4-Cl-Ph analogue of 7c had a C. albicans MIC = 0.016 µg/mL), the 2,4-
difluorophenyl moiety consistently furnished superior potency. Small meta/para-disubstituents at the R
position of 2 provided inferior potency compared to 7c as well (e.g., the racemic 3,4-diF-Ph analogue of 7c
had a C. albicans MIC = 0.016 µg/mL). Ether 7d exhibited marked affinity for C. albicans-CYP51 with Kd <
0.039 µM (>2200-fold yeast selectivity v. human CYP51, manuscript in preparation). The in vitro safety
profiles of 7c and 7d (CYP3A4 IC50 = 79 µM and 65 µM, respectively; Table 3) were superior to marketed
azoles such as itraconazole (CYP3A4 IC50 = 0.07 µM). Additionally, ether 7d exhibited weak activity for
CYP2C9 (IC50 = 99 µM) and CYP2C19 (IC50 = 72 µM). These highly-selective CYP51 inhibitors (e.g., 7a-d)
are, in general, extremely resistant to liver CYP metabolism. For example, ether 7d was recovered in >99%
yield following 2 hour incubations in animal and human liver microsome preparations, and has a long oral
half-life in humans (>> 24 hours; manuscript in preparation) desired for an infectious disease therapeutic.
Orally-administered 7d was highly-active in in vivo models of yeast and dermatophyte infection. In a mouse
invasive candidiasis model, a single oral dose of 10 mg/kg 7d reduced kidney fungal burden by 99%.14 In a
guinea pig dermatophytosis model (T. mentagrophytes),18 7d provided 86% mycological efficacy following 9
daily, oral doses of 10 mg/kg.

Table 3. Antifungal Activity of Difluoromethyl-Pyridyl-Benzenes.
7
C. albicans
MICa
T. rubrum
MICa
CYP3A4
b
IC50
Selectivity
Indexc
9,000
Compound
R
Cl
36
7a
<0.001
<0.001
<0.001
<0.001
0.016
0.004
0.002
CF3
54
27,000
>79,000
>65,000
1.1
7b
OCF3
OCH2CF3
-
79
7c
7d
<0.001
<0.001
0.062
65
0.07
Itraconazole
a. Minimum concentration that achieved 50% inhibition of fungal growth; MIC units in µg/mL.5 b. Inhibition
of CYP3A4 measured in microsomes obtained from pooled human hepatocytes, IC50 units in µM.8 c. In vitro
selectivity calculated as CYP3A4 IC50 / T. rubrum MIC.
In summary, we have described the design and synthesis of novel, potent, and highly selective, 1-
tetrazole based fungal CYP51 inhibitors.19 A representative of this chemical series, VT-1161 (7d), has
advanced into human clinical trials and exhibited linear pharmacokinetics coupled with excellent tolerability
in an oral, multiple-ascending dose, Phase 1 study.4 The MBG-based design process described herein is
broadly applicable to the discovery of new, potent and selective inhibitors of the metalloenzyme target class.
The same approach has produced highly-selective CYP17 inhibitors as potential treatments for prostate
cancer20,21 in addition to the fungal CYP51 inhibitors described herein.4
Acknowledgements. We thank Professors Thomas O’Halloran and Holden Thorp for their insightful
guidance, and Mr. Sammy R. Shaver for assistance with the homology model.
References and Notes
1. Podust, L.M.; Poulos, T.L.; Waterman, M.R. Proc. Nat. Acad. Sci. 2001, 98(6), 3068-3073.
2. Lewis, R.E. Mayo Clin. Proc. 2011, 86(8), 805-817.
3. Pitman, S.K.; Drew, R.H.; Perfect, J.R.; Expert Opin. Emerging Drugs 2011, 16(3), 559-586.
4. Schotzinger, R.J.; Degenhardt, T.P.; Wargin, W.A.; Still, J.G.; Gutierrez, M.J. “A Phase 1 Multiple-
Ascending-Dose Trial of VT-1161, a Highly Potent and Selective Oral Antifungal Agent for the
Treatment of Superficial Fungal Infections.” Abstract #7516, Am. Acad. Dermatology Summer Academy
Meeting, August 2, 2013.
5. Minimum inhibitory concentrations (MIC) for standard ATCC isolates were determined under the CLSI
guidelines M27-A3 (for yeasts such as C. albicans) and M38-A2 (for dermatophytes such as T. rubrum)
and were read at 50% inhibition of fungal growth (Ricerca Biosciences, LLC).

6. Compounds were synthesized as anti-racemates. For the synthetic method, see Dickinson, R.P.; Bell,
A.S.; Hitchcock, C.A.; Narayanaswami, S.; Ray, S.J.; Richardson, K.; Troke, P.F. Bioorg. Med. Chem.
Lett. 1996, 6(16), 2031-2036.
7. In silico enthalpies were also determined which generally aligned with in silico pKas. Briefly, 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 CYP51 Fe-porphyrin
construct1 was minimized (MMFF-94) and then optimized using the PM3 semi-empirical method to
obtain an unligated structure. Me-MBGs were introduced and the energy was determined by a single
point calculation. The Fe-porphyrin and Me-MBG were complexed with only the Me-MBG ligand free to
move during optimization. Next, the Me-MBG was submitted for geometry optimization and enthalpy
measured. For the 1-imidazole and the 1-(1,2,4-triazole), the enthalpy values were determined to be -18.9
and -16.5 kcal/mol, respectively.
8. IC50 values for CYP3A4 enzyme were determined in human hepatocyte microsomes using 150 µM
testosterone as substrate (a concentration equal to the Km determined in the same lab). Reactions were
analyzed for product using HPLC/MS/MS methods and IC50 values (in µM) were determined by fitting a
4-parameter logistical fit to the dose response data (OpAns, LLC).
9. Shakeri-Nejad, K.; Stahlmann, R. Expert Opin. Pharmacother. 2006, 7(6), 639-651.
10. Denning, D.W.; Hope, W.W. Trends Microbiology 2010, 18(5), 195-204.
11. Homology modeling was conducting using Molecular Operating Environment (MOE; Chemical
Computing Group, 1010 Sherbrooke St. W, Suite 910 Montreal, Quebec, Canada H3A 2R7). A series of
homology models was constructed using the sequence information for Candida albicans and CYP51
crystal structures deposited in the Protein Data Bank. The model chosen for evaluation was developed
from a Trypanosoma cruzi crystal structure with posaconazole bound (3K1O; Lepesheva, G.I.; Hargrove,
T.Y.; Anderson, S.; Kleshchenko, Y.; Furtak, V.; Wawrzak, Z.; Villalta, F.; Waterman, M.R. J. Biol.
Chem. 2010, 285(33), 25582–25590). The homology model was then created using Amber99 as the
protein modeling forcefield and PFROSST as the forcefield for energy minimizations, with a final RMS
gradient of 0.5.
12. Eto, H.; Kaneko, Y.; Sakamoto, T. Chem. Pharm. Bull. 2000, 48(7), 982-990.
13. Female CD-1 mice (7 weeks, 18-25 g) were made neutropenic with IP injections of cyclophosphamide
(150 mg/kg) at 4 and 1 days before inoculation with C. albicans R303 via the tail vein. Compounds were
administered orally 2 h after infection on day 1. Kidneys were collected from treated mice on day 2, PBS
added, and then homogenized. Colony-forming units (CFU)/kidney were determined from number of
colonies detected on SDA plates from serial dilutions of the homogenates. Fluconazole was used as a
positive control and reduced kidney fungal burden 99% when orally dosed at 10 mg/kg (Ricerca
Biosciences, LLC).
14. Hoekstra, W.J.; Schotzinger, R.J. PCT Int. Appl. 2012, WO2012177725.
15. Compound 2f was synthesized from 3 as follows16: To a suspension of Cu powder (2.68 g, 42.2 mmol) in
DMSO (35 mL) was added ethyl bromodifluoroacetate (2.70 mL, 21.10 mmol), and the mixture was
stirred for 1 h at RT. 2,5-Dibromopyridine (2.50 g, 10.55 mmol) was then added and stirring continued
for 15 h at RT. The reaction was quenched with aqueous NH4Cl and extracted with DCM (3 x 25 mL).
The combined organic layers were washed with water and brine, dried over anhydrous (Na2SO4), and
concentrated to afford a crude product mixture which upon column purification (EtOAc/hexane) afforded
the ethyl ester intermediate (2.40 g, 8.57 mmol, 81%) as a pale yellow oil. To a stirred solution of 2,4-
difluoro-bromobenzene (1.65 g, 8.57 mmol) in diethyl ether (10 mL) was added n-BuLi (3.70 mL, 8.57
o
mmol) at -70 C followed by addition of ester (2.40 g, 8.57 mmol) in diethyl ether (5 mL) after 15
o
minutes. The reaction mixture was stirred for 1 h at -70 C and warmed to RT and stirred 2 h. The
reaction was quenched with aqueous NH4Cl solution and extracted with EtOAc (3 x 20 mL). The
combined organic layers were washed with water, washed with brine, dried (Na2SO4), and concentrated.
The crude compound was purified by column chromatography to afford ketone 4 (1.30 g, 3.73 mmol,
43%) as a yellow liquid. To a stirred solution of ketone 4 (1.30 g, 3.73 mmol) in diethyl ether (300 mL)
was added freshly prepared diazomethane at 0 oC followed by warming to RT. The reaction mixture was
stirred for 2 h. The volatiles were removed to afford a crude product mixture which upon column

chromatography (EtOAc/hexane) afforded oxirane 5 (800 mg, 2.20 mmol, 59%) as light yellow solid. To
a stirred solution of oxirane 5 (0.25 g, 0.69 mmol) in THF (20 mL) and water (7 mL) were added 4-
(trifluoromethyl)phenylboronic acid (0.10 g, 0.55 mmol), Na2CO3 (0.16 g, 1.55 mmol) and Pd(dppf)2Cl2
(0.14 g, 0.17 mmol) at RT under argon. After purge with argon for a period of 30 min, the reaction
mixture was heated to 75°C and stirring was continued for 4 h. The reaction mixture was cooled to RT
and filtered through celite. The filtrate was concentrated to a residue and re-dissolved in EtOAc (30 mL).
The organic layer was washed with water and brine, dried (Na2SO4), and concentrated. The crude
compound was purified by column chromatography to afford 6f (0.21 g, 0.49 mmol, 71%) as a white
solid. To a stirred solution of 6f (0.42 g, 0.98 mmol) in DMF (10 mL) was added K2CO3 (67 mg, 0.49
mmol) followed by 1H-tetrazole (68 mg, 0.98 mmol) at RT under argon. The reaction mixture was stirred
for 5 h at 80 °C. The volatiles were removed in vacuo and the obtained residue was dissolved in EtOAc
(30 mL). The organic layer was washed with water and brine, dried (Na2SO4), and concentrated. The
crude compound was purified by column chromatography to afford 2f (0.14 g, 0.28 mmol, 29 %) as a
1
white solid. H NMR (500 MHz, CDCl3): δ 8.76 (s, 1 H), 8.73 (s, 1 H), 8.01 (dd, J = 8.0, 2.0 Hz, 1 H),
7.78 (d, J = 8.5 Hz, 2 H), 7.72-7.67 (m, 3 H), 7.49 (s, 1 H), 7.44-7.37 (m, 1 H), 6.81-6.76 (m, 1 H), 6.71-
6.65 (m, 1 H), 5.57 (d, J = 14.0 Hz, 1 H), 5.19 (d, J = 14.0 Hz, 1 H). HPLC: 97.3%. Mass: m/z 498
[M++1]. (R)-(+)-Enantiomers (7a-7d) were isolated from racemates using chiral chromatography.
16. Hoekstra, W.J.; Schotzinger, R.J.; Rafferty, S.W. U.S. Patent 8,236,962 issued Aug. 7, 2012.
17. A single-crystal x-ray diffraction method was employed to assign the (R)-absolute configuration of both
7c and 7d [all opposite, (-)-enantiomers of 7a-7d exhibited immeasurable MICs].
18. Ghannoum, M.A.; Hossain, M.A.; Long, L.; Mohamed, S.; Reyes, G.; Mukherjee, P.K. J. Chemotherapy
2004, 16(2), 139-144. Itraconazole was used as a positive control and reduced skin fungal burden by 69%
when dosed orally 10 mg/kg QD for 9 days.
19. Recent CYP51 publications provide further insights into the design of potentially-selective CYP51
inhibitors. For T. cruzi and S. cerevisiae structural insights, respectively, see the following two references.
a) T. Y. Hargrove et al. J. Biol. Chem. 2013, 288(44), 31602-31615. b) B. C. Monk et al. Proc. Natl.
Acad. Sci. USA 2014, 111(10), 3865-3870.
20. a) Abbott, D.H.; Eisner, J.R.; Bird, I.M.; Rafferty, S.W.; Moore, W.R.; Schotzinger, R.J. “Plasma Steroid
Concentrations in Male Rhesus Monkeys Following Treatment with the P450c17 (CYP17) Inhibitors VT-
464 and Abiraterone Acetate: A Comparison to Human 17,20-Lyase (lyase) and Combined Lyase/17α-
Hydroxylase Deficiencies.” Endocr. Rev. 2012, 33: SAT-256. b) Eisner, J.R.; Abbott, D.H.; Bird, I.M.;
Rafferty, S.W.; Moore, W.R; Schotzinger, R.J. “Assessment of Steroid Hormones Upstream of P450c17
(CYP17) in Chemically Castrate Male Rhesus Monkeys Following Treatment with the CYP17 Inhibitors
VT-464 and Abiraterone Acetate (AA).” Endocr. Rev. 2012, 33: SAT-266.
21. Rafferty, S.W.; Eisner, J.R.; Moore, W.R.; Schotzinger, R.J.; Hoekstra, W.J. “Highly-Selective 4-(1,2,3-
Triazole)-Based P450c17a 17,20-Lyase Inhibitors” Bioorg. Med. Chem. Lett. 2014, 24, 2444-2447.

Graphical Abstract
Design and Optimization of Highly-Selective Fungal CYP51
Inhibitors
William J. Hoekstra, Edward P. Garvey, William R. Moore, Stephen W.
Rafferty, Christopher M. Yates, and Robert J. Schotzinger
(MBG = metal-binding group)

Schemes
F
F
HO
N
N
N
N
F
N
R
F