Rational design and synthesis of 4-((1R,2R)-2-hydroxycyclohexyl)- 2(trifluoromethyl)benzonitrile (PF-998425), a novel, nonsteroidal androgen receptor antagonist devoid of phototoxicity for dermatological indications

Article abstract of DOI:10.1021/jm8009316

4-((1R,2R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)-6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)-6a. was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.

Full text of DOI:10.1021/jm8009316

7010
J. Med. Chem. 2008, 51, 7010–7014
Rational Design and Synthesis of 4-((1R,2R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile
(PF-998425), a Novel, Nonsteroidal Androgen Receptor Antagonist Devoid of Phototoxicity for
Dermatological Indications
Jie Jack Li,*,† Donna M. Iula,†,# Maria N. Nguyen,†,O Lain-Yen Hu,†,O Danielle Dettling,‡,[ Theodore R. Johnson,|,∞
Daniel Y. Du,‡,O Veerabahu Shanmugasundaram,†,O Jennifer A. Van Camp,†,× Zhi Wang,†,# William G. Harter,†,¶
Wen-Song Yue,†,X Mark L. Boys,†,] Kimberly J. Wade,‡,4 Elena M. Drummond,‡,O Brian M. Samas,§,O Bruce A. Lefker,§,O
Garrett S. Hoge,§,b Mark J. Lovdahl,§,@ Jeffrey Asbill,‡,O Matthew Carroll,‡,O Mary Ann Meade,‡, Susan M. Ciotti,§,¢ and
,3
Theresa Krieger-Burke
Departments of Chemistry, Dermatology Biology, Pharmaceutical Sciences, Pharmacokinetics and Drug Metabolism, and Drug Safety,
Michigan Laboratories, Pfizer Global Research & DeVelopment, 2800 Plymouth Road, Ann Arbor, Michigan 48105
ReceiVed July 30, 2008
4-((1R,2R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)-6a] is a novel, nonsteroidal
androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective,
and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted
systemic side effects due to its primary pharmacology. (-)-6a was tested negative in the 3T3 NRU assay,
validating our rationale that reduction of conjugation might reduce potential phototoxicity.
Introduction
The androgen receptor (ARa) is a ligand-activated nuclear
hormone receptor. Nonsteroidal AR antagonists, in turn, have
been extensively investigated during the past 2 decades.1,2 The
* To whom the correspondence should be addressed. Present address:
Discovery Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway,
Wallingford, CT 06492. Phone: (203) 677-7225. E-mail: jack.li@bms.com.
†
Department of Chemistry.
Present address: Process Exploration, Cayman Chemical Company,
#
1180 East Ellsworth Road, Ann Arbor, Michigan 48108.
O
Present address: Pfizer Global Research and Development, Eastern
Point Road, Groton, CT 06340.
‡
Department of Dermatology Biology.
Present address: Research Technology Center, Pfizer Global Research
[
Figure 1. Known nonsteroidal androgen receptor antagonists.
& Development, 620 Memorial Drive, Cambridge, MA 02139.
|
Department of Pharmacokinetics and Drug Metabolism.
Present address: Pfizer Global Research & Development, 10777 Science
∞
fruits of research and development in the field are exemplified
by several marketed drugs as androgen receptor antagonists.
Flutamide (1, Figure 1) was launched in 1983 by Schering-
Plough for the treatment of prostate cancer.3 Sanofi-Aventis’
nilutamide (2) and AstraZeneca’ bicalutamide (3) gained
regulatory approval as a prostate cancer therapy in 1987 and
1993, respectively.4 In addition, dozens of nonsteroidal AR
antagonists are in various stages of clinical trials for an array
of indications.
Center Drive, San Diego, CA 92121.
×
Present address: Hit to Lead Chemistry, Global Pharmaceutical R&D,
Abbott Laboratories, 200 Abbott Park Road, Abbott Park, IL 60064-6217.
¶
Present address: Norac Pharma, 405 S. Motor Avenue; Azusa, CA
91702.
X
Present address: School of Pharmacy, Ohio State University, 500 W
12th Avenue, Columbus, Ohio 43210.
]
Present address: Chemistry Department, Array BioPharma Inc., 3200
Walnut Street, Boulder, CO 80301.
4
Present address: Pfizer Global Research & Development, 800 N.
Lindbergh, Creve Coeur, MO, 63141.
AR is known to be responsible for the activation of genes
involved in the pathogenesis of acne and alopecia.5 Androgens,
such as testosterone and dihydrotestosterone (DHT), play a key
role in the function of sebaceous glands and hair follicles and
are major contributors to the pathogenesis of androgenetic
alopecia in genetically susceptible male and female subjects.
For instance, prepubertal gonadectomy of male subjects prevents
recession of scalp hair. A recent clinical study demonstrated
that flutamide (1) significantly reduced hair loss in female
androgenetic alopecia patients.6 Compound 4, a potent AR
inhibitor, also showed promise for the treatment of androgenetic
alopecia.7 On the other hand, under the influence of androgens,
the sebaceous glands become larger and produce more sebum.
Cyproterone acetate8 and spironolactone,9 used in women as
oral contraceptives, significantly reduced the sebum excretion
§
Department of Pharmaceutical Sciences.
Present address: Solvias AG, P.O. Box Postfach, Klybeckstrasse 191,
b
4002 Basel, Switzerland.
@
Present address: Process R&D, Bristol-Myers Squibb Company, 1
Squibb Drive, New Brunswick, NJ 08901.
Present address: MIR Preclinical Services, 800 Technology Drive, Ann
Arbor, MI 48108.
¢
Present address: NanoBio Corporation, 2311 Green Road, Suite A, Ann
Arbor, Michigan 48105.
Department of Drug Safety.
Present address: In Vivo Pharmacology Center, Michigan State
3
University, East Lansing, MI 48824.
a Abbreviations: API, active pharmaceutical ingredients; AR, androgen
receptor; b.i.d., twice daily; CYP, cytochrome P450; DDI, drug-drug
interaction; DHT, testosterone and dihydrotestosterone; ee, enantiomeric
excess; EH, extraction ratio; HTS, high-throughput screen; NRU, neutral
red uptake; q.d., once daily; SAR, structure-activity relationship; TFA,
trifluoroacetic acid.
10.1021/jm8009316 CCC: $40.75
2008 American Chemical Society
Published on Web 10/16/2008

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 21 7011
cyclohexanone with the aid of NaH to give the desired
C-arylated product 8 as the minor product (26% yield), with
the major product as the O-arylated vinyl ether adduct [4-(cy-
clohex-1-enyloxy)-2-trifluoromethylbenzonitrile, 52% yield; see
Supporting Information]. The resulting ketone 8 was reduced
to alcohol 6 using NaBH4 to give the cis-isomers 6a as the minor
product (31%) and the trans-isomer 6b as the major product
(64%). While trans-isomer 6b was inactive in the AR binding
assay, the cis-alcohol 6a was active in the AR binding and the
cellular assays. Further separation of the two enantiomers of
the cis-alcohol 6a using chiral HPLC provided (-)-6a (PF-
998425) and (+)-6a, respectively. While (+)-6a was essentially
inactive in the AR binding assay, (-)-6a was active in AR
binding and cellular assays with IC50 values of 37 and 43 nM,
respectively. A chiral carbamate 9 was prepared by treating (-)-
6a with (R)-1-(1-isocyanatoethyl)naphthalene, and the single
crystal X-ray crystallography of 9 (Figure 4) determined that
the absolute configuration of (-)-6a was (1R,2R).
Preliminary in vitro evaluation of the activity, metabolic
stability, and safety characteristics of (-)-6a proved favorable;
consequently, a more efficient synthesis was mandated to
prepare enough active pharmaceutical ingredients (API) to
support subsequent in vivo studies. To that end, we carried out
a halogen/metal exchange of 4-iodo-2-(trifluoromethyl)benzoni-
trile using n-BuLi followed by treatment with cyclohexanone
to afford tertiary alcohol 10 (Scheme 2). Exposure of 10 to neat
trifluoroacetic acid (TFA) gave rise to olefin 11, which was then
subjected to an asymmetric epoxidation using Jacobsen’s (S,S)-
Mn(III)-salen complex as the catalyst to give epoxide 12 in 94%
ee.19 Epoxide 12 was subsequently hydrogenated to deliver (-)-
6a in 57% yield for the two steps with 94% ee. The aforemen-
tioned synthesis allowed preparation of a large quantity of API
to complete a panel of in vivo investigations (vide infra).
Figure 2. Rational design in reducing the conjugation of the molecule.
rate and decreased the severity of acne. 4 was proven to be
efficacious in reducing sebum production in the animal models.10
Regrettably the approach to stop or reverse male pattern
baldness using systemic antiandrogens (androgen blockade or
androgen receptor antagonism) has not been pursued because
of the feminizing effect and interference with male sexual
functions. In contrast, a topical product is preferred over an oral
agent because of a lower risk of side effects stemming from
systemic exposure. To that end, our laboratories set out to
discover androgen receptor antagonists as treatments for skin
related disorders including sebum control and hair growth. We
preferred the topical drugs that are active topically and yet
devoid of systemic pharmacological activities to avoid deleteri-
ous side effects.
Our high-throughput screen (HTS) was carried out with a
[3H]DHT competitive ligand binding assay using the human
full-length AR as the primary assay.11 Compounds active (IC50
< 100 nM) in the binding assay were further screened using
the MDA-MB-453-MMTV-luci cell line as the secondary assay
(IC50 < 100 nM).12 From our compound library, we derived a
series of diarylphenols as exemplified by 5a and 5 b. In vitro,
their IC50 values were 40 ( 19 and 37 ( 13 nM, respectively.
And their IC50 values in an AR cellular functional assay were
0.022 and 8.1 nM, respectively. Both compounds also demon-
strated greater than 100-fold selectivity against the estrogen and
progesterone receptors in vitro. In the in vivo sebum model using
male Golden Syrian hamster ear,13 5a and 5b were active and
reduced the production of wax ester, a mechanism biomarker
for sebum reduction, by 86% and 87%, respectively, at a 3%
dose in a vehicle of 70:30 ethanol/propylene glycol.14 Unfor-
tunately they were tested positive in the 3T3 neutral red uptake
(NRU) phototoxicity test,15,16 indicating a high risk for causing
photoirritation. Consequently, they were deemed unsuitable as
topical drugs. Although the correlation between phototoxicity
and high conjugation in topical drug molecules has not been
systematically investigated, the fundamentals of photochemistry
prompted us to rationalize that reduction of the conjugation of
a molecule might lower the risk of phototoxicity. Thus, we
designed an AR antagonist resembling 6, where the phenol ring
in 5a was replaced with a cyclohexanol (Figure 2). Molecular
modeling17,18 of 6 in the crystal structure of the ligand-binding
domain of the androgen receptor indicated favorable interactions
as shown in Figure 3. The structural modifications led to the
preparation and evaluation of a novel, potent, selective AR
antagonist (-)-6a that was also active in vivo and devoid of
the phototoxicity consistently seen for biarylphenols such as
5a and 5b.
Structure-Activity Relationship (SAR) and Selectivity
We chose 4 as our reference compound because it was
efficacious in vivo for hair growth and sebum reduction.7 Again,
the AR binding assay was carried out with the [3H]DHT
competitive ligand binding assay using the human full-length
AR and the AR cellular assay was carried out with the MDA-
MB-453-MMTV-luci cell line. Because of the high homology
at the ligand-binding region between androgen receptor and
progesterone receptor (80-90%), the progesterone receptor
binding assay was conducted according to the manufacture’s
manual using the commercial kit.20 As shown in Table 1, biaryls
5a and 5b were active in the AR binding and cellular assays
and were especially potent in the AR cellular assay. Our initial
hit aminopyridylnitrile 13 was also tested active in the AR
binding and cellular assays.10 Unfortunately, 5a, 5b, and 13 were
not further pursued for their dermatological indications because
they were all tested positive in the 3T3 neutral red uptake (NRU)
phototoxicity test, indicating a high risk for causing photoirri-
tation. As far as our rationally designed arylcyclohexanols were
concerned, the trans-isomer 6b was inactive in our AR binding
assay although the racemic cis-isomer 6a had IC50 values of 26
and 90 nM in the AR binding and cellular assays, respectively.
After separation of the racemate 6a, (+)-6a (1S,2S) was tested
inactive in our AR binding assay although the enantiomer (-)-
6a (1R,2R) had IC50 values of 37 and 43 nM for the AR binding
and cellular assays, respectively.
With potent AR antagonists in hand, we proceeded to
investigate their selectivity against other nuclear hormone
receptors. Compound (-)-6a had low binding affinity to the
progesterone receptor (IC50 > 10 µM), demonstrating a greater
Chemistry and in Vitro Activity
Our initial synthesis of 6 (Scheme 1) commenced with
condensation of 4-fluoro-2-(trifluoromethyl)benzonitrile (7) with

7012 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 21
Brief Articles
Figure 3. (Left) Model of 6 (cyan) in the crystal structure of AR W741L ligand-binding domain (orange backbone). Bicalutamide (3) is shown
in yellow for reference. Key side chain residues are displayed in green. Trp741 from WT AR crystal structure is shown in white for reference.
(-)-6a forms favorable interactions with Arg752, Gln711, and Leu. (Right) Trp741 and Met 745 are shown in CPK rendering to indicate contacts
with (-)-6a which destabilizes the WT AR LBD conformation and stabilizes W741L mutant AR LBD conformation.
Scheme 1. Orginal Synthesisa
Scheme 2. Improved Synthesisa
a Reagents and conditions: (a) n-BuLi, THF, -78 °C, then cyclohex-
anone, THF, -78 °C f room temp, overnight; (b) TFA, 60 °C, 4.5 h,
58%, two steps; (c) (S,S)-Jacobsen’s Mn(III)-salen chiral catalyst {[[(N,N′-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]manganese(III)]
chloride}, NaOCl, 4-phenylpyridine N-oxide, CH2Cl2, 0 °C, overnight; (d)
H2 (50 psi), Pd/C, MeOH, Et3N, 7 h, 57%, two steps.
a Reagents and conditions: (a) cyclohexanone, NaH, DME, reflux, 1 h,
31%; (b) NaBH4, MeOH, 24 h, 95% (64% for 6b, 31% for 6a).
apparent of volume of distribution at steady state was 6.5 L/kg,
and the mean terminal phase half-life was 2.6 h.22
We proceeded to investigate the drug’s safety profile. As we
predicted, (-)-6a tested negative in the 3T3 neutral red uptake
(NRU) phototoxicity test, a desired attribute for a dermatology
drug. The risk for QT elongation was low because there was
no detectable activity in the dofetilide binding assay. Since there
is a direct correlation between wax ester reduction and a
reduction in total sebum production,23,24 the drug was found to
be active in vivo in male Golden Syrian hamster ear model for
sebum reduction (Figure 6).13 At 3% concentration in 70:30
ethanol/propylene glycol, (-)-6a reduced sebum by 85%.
Its estimated ED50 was 0.4% in the male Golden Syrian hamster
ear model for sebum reduction when tested in a vehicle of
ethanol/propylene glycol (70/30, v/v). In comparison, at 3%
concentration, reference 4 reduced sebum by 92% and ami-
nopyridine 83%, respectively. On the other hand, it seems that
the relative in vivo efficacy for sebum reduction may correspond
to the potency in cellular assay. For instance, one of our lead
compounds, 14 with an IC50 of 12 nM in the AR cellular assay
and an ED50 value of 0.1%,25 was more efficacious than (-)-
6a, which had IC50 of 43 nM in the AR cellular assay and an
ED50 value of 0.4%. Despite the less efficacious than 14, (-)-
6a provides an alternative candidate with a unique overall
profile, especially considering that severe reduction of sebum
could cause dry skin. Finally, (-)-6a was evaluated and found
to be active in the C3H/HeN mouse hair growth model (see
Supporting Information).26
Figure 4. ORTEP plot of carbamate derivative 9.
than 100-fold selectivity. Subsequently, (-)-6a had low binding
affinities when screened against a panel of common receptors
and enzymes.
Pharmacokinetics, in Vivo Activity, and Safety
Ideally, topical drugs exert their desired effects locally but
are rapidly inactivated via metabolism once they reach the
systemic circulation, thereby reducing unwanted systemic ef-
fects. The pharmacokinetic characteristics of (-)-6a were
favorable for a topical agent. Compound (-)-6a was rapidly
metabolized in rat liver microsomes (t1/2 ) 4 min, CLint ) 350
(µL/min)/mg protein). The hepatic extraction ratio (EH) predicted
from these in vitro data approached liver blood flow in rat, with
a predicted EH value of 0.90.21 In vivo clearance data in dogs
were consistent with the high clearance predicted in vitro in rat
(see Figure 5). Following intravenous administration of (-)-
6a, mean systemic plasma clearance was 40 (mL/min)/kg. This
value was similar to hepatic blood flow in this species, indicating
that (-)-6a is a high clearance compound in dogs. The mean
In summary, we designed and synthesized a novel, nonste-
roidal AR antagonist (-)-6a for the sebum control and treatment

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 21 7013
Table 1. SAR and Selectivity of the Benzonitrile Series
Figure 6. Dose response relationship of (-)-6a and sebum wax ester
content in the male Golden Syrian hamster ear model: 1, vehicle control
(70:30 ethanol/propylene glycol); 2, 0.03% (-)-6a (b.i.d.); 3, 0.1% (-)-
6a (b.i.d.); 4, 0.3% (-)-6a (b.i.d.); 5, 1% (-)-6a (b.i.d.); 6, 3% (-)-
6a (b.i.d.); 7, 1% 4 (b.i.d.); 8, 1% 4 (q.d.); 9, untreated.
analysis for hamster ear samples; C3H/HeN mouse hair growth
model and histological analysis of hair follicular changes in C3H
mice; single X-ray crystallographic coordinates of 9; experimental
conditions for androgen receptor binding assays; androgen receptor
cellular assays; C3H/HeN mouse hair growth model; male Syrian
hamster ear model for sebum reduction; metabolic stability in rat
liver microsomes; pharmacokinetics in dogs; molecular modeling;
lipid extraction and HPLC-ELSD methodology; mobile phase
gradient utilized for separation of sebum components in HPLC-
ELSD method; C3H/HeN mouse hair growth model; histological
analysis of hair follicular changes in C3H mice. This material is
available free of charge via the Internet at http://pubs.acs.org.
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