Pantolactams as androgen receptor antagonists for the topical suppression of sebum production

Article abstract of DOI:10.1016/j.bmcl.2011.07.048

A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to

Full text of DOI:10.1016/j.bmcl.2011.07.048

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5230–5233
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pantolactams as androgen receptor antagonists for the topical suppression of
sebum production
Karen E. Sexton a, , Stephen Barrett a, Katy Bridgwood a, Matthew Carroll b, Danielle Dettling b, Daniel Du b,
⇑
Stephen Fakhoury a, Victor Fedij a, Lain-Yen Hu a, Catherine Kostlan a, David Pocalyko b, Neil Raheja a,
b
Yvonne Smith c, Veerabahu Shanmugasundaram d, , Kimberly Wade
⇑
a Department of Medicinal Chemistry, Michigan Laboratories, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
b Dermatology Biology, Michigan Laboratories, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
c Lead Discovery Technologies, Michigan Laboratories, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
d Computer-Assisted Drug Discovery, Michigan Laboratories, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of pantolactam based compounds were identified as potent antagonists for the androgen recep-
tor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated
Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major
component of sebum, initiating further preclinical work on these compounds.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 23 May 2011
Revised 11 July 2011
Accepted 12 July 2011
Available online 23 July 2011
Keywords:
Androgen receptor
Antagonist
Sebum
Topical
AR
The androgen receptor (AR) plays a role in the regulation of se-
bum production and is implicated in the pathogenesis of acne and
O2N
F3C
NC
F
O
alopecia.1 Activation of AR by androgens testosterone and 5
a
-dihy-
N
H
O
F3C
N
H
S
O2
HO
drotestosterone (5a-DHT) leads to the enlargement of the seba-
ceous gland and the production of more sebum, which can in
turn lead to acne vulgaris infections. Known androgen receptor
antagonists include prostate cancer therapies (flutamide2 [1], nilu-
tamide3 [2], R-bicalutamide4,5 [3]) and oral contraceptives. (Fig. 1)
Oral contraceptives cyproterone acetate6,7 and spironolactone8
have been shown to significantly reduce sebum production and de-
crease the severity of acne. RU-58841, 4, a potent inhibitor of AR,
showed promise for the treatment of androgenetic alopecia and
was efficacious in reducing sebum production in an animal model.9
Unfortunately, treatment of male pattern baldness with systemic
AR antagonists resulted in unwanted feminizing effects and inter-
ference with male sexual functions. Our lab, therefore, sought to
identify topically delivered non-steroidal AR antagonists for the
control of excess sebum production devoid of such side effects by
minimizing systemic exposure.
3, bicalutamide
1, flutamide
O2N
F3C
NC
OH
O
O
N
F3C
N
N
NH
O
O
2, nilutamide
4, RU-58841
Figure 1. AR antagonists.
In our search for novel topical androgen receptor antagonists10–
we identified lactone based compounds, exemplified by com-
pound 5 (Table 1). The R enantiomer 5–2 was efficacious in reduc-
ing sebum in an animal model. These compounds bind efficiently
to the androgen receptor and act as antagonists.
16
⇑
Corresponding authors. Present address: WorldWide Medicinal Chemistry,
Pfizer Worldwide Research & Development, Sandwich CT13 9NJ, UK (K.E. Sexton).
E-mail addresses: karen.sexton@hotmail.co.uk (K.E. Sexton), veerabahu.
shanmugasundaram@pfizer.com (V. Shanmugasundaram).
Compound 5–2 existed as a mixture of the lactone and ring
opened hydroxy acid resulting from the hydrolysis of the lactone.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.07.048

K. E. Sexton et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5230–5233
5231
Table 1
MeO
OMe
Biological activity of pantolactones
O
NC
NC
O
NH
a
O
O
NC
NC
O
+ H2O
- H2O
CO2H
F3C
O
F3C
O
OH
F3C
O
F3C
O
OH
5
6
5
b, c
MeO
R
OMe
O
O
d, e
NC
NC
N
N
Compound
Stereocenter
ARB (nM)
ARCELL (nM)
5–1
5–2
5–3
Racemic
R-(+)
S-(À)
113
70
10,000
70
42
1000
F3C
O
8
F3C
O
7
Scheme 2. Reagents and conditions: (a) 4-methoxybenylamine, MeOH, rt, 96%; (b)
MsCl, pyr, 0 °C–rt, 97%; (c) NaH, THF, rt, 65%; (d) TFA, Et3SiH, reflux, 70%; (e) NaH,
R–X, THF.
Values (IC50) are given as an average of P2 experiments; ARB, human androgen
receptor binding assay; ARCELL, human androgen receptor cellular functional assay.
Table 2
R
O
O
SAR of racemic pantolactams based on 8
NC
NC
N
O
Compound
R
ARB (nM)
ARCELL (nM)
F3C
O
F3C
O
9
H
Me
Et
nPr
nBu
nPent
nHex
CH(Me)nPr
(+)-CH(Me)Et
(À)-CH(Me)Et
CH2CH(Et)2
(4-Me)nPent
CH2OMe
(CH2)2OMe
(CH2)2SMe
(CH2)3OH
CH2CO2Me
CH2CO2Et
CH2CONHEt
CH2Ph
2790
1210
399
188
119
268
766
200
132
9790
444
802
516
1770
2450
523
494
3520
4910
30
82
—
—
24
16
—
—
6
32
—
—
—
—
—
—
—
—
10
11
12
13
14
15
16
17a
18a
19
20
21
22
23
24
25
26
27
28
PG
O
O
NC
N
O
F3C
F
HO
HO
Scheme 1. Retrosynthetic analysis.
Due to the rapid interconversion and equilibrium between the two
forms, we were unable to envision a development path forward for
the lactone derivatives. The replacement of the lactone moiety
with a lactam would prevent facile ring opening and enable SAR
to be developed through functionalization of the lactam ring
nitrogen.
—
11
Herein we describe the synthesis and evaluation of a series of
pantolactams analogous to pantolactone 5.17 Encouraged by race-
mic pantolactone 5–1 activity in both the binding and functional
assays, racemic pantolactam compounds were synthesized for ini-
tial SAR studies facilitating rapid analog production. Two synthetic
approaches were evaluated to obtain target pantolactam com-
Values (IC50) are given as an average of P2 experiments; —, not tested; ARB,
human androgen receptor binding assay; ARCELL, human androgen receptor cel-
lular functional assay.
a
Synthesized from appropriate (a)-methylbenzyl amine.
pounds both incorporating diversification as
a final step
(Scheme 1). The first involved synthesis of hydroxypantolactam
followed by SNAr reaction with 4-fluoro-2-(trifluoromethyl)-benzo-
nitrile under basic conditions to provide the desired lactam. Alter-
natively, the lactone moiety of compound 5–1 could be converted
to the pantolactam ring. The latter route was selected for the syn-
thesis of pantolactam analogs and is displayed in Scheme 2. Panto-
lactone 5–1 was converted to the ring opened hydroxy-amide (6).
Conversion of the hydroxyl group to a mesylate with subsequent
ring closure yielded the dimethoxybenzyl (DMB) protected panto-
lactam (7). After removal of the DMB protecting group, the inter-
mediate was appropriately substituted to provide the target
compounds (8).
We envisioned an abbreviated synthetic sequence by using the
appropriate amine in Step 1, preventing a protection/deprotection
sequence once active compounds were identified. Other stereospe-
cific synthetic methods16,18 were utilized once enantiopure com-
pounds were identified for further preclinical testing.
clic groups. Subsequent libraries expanded on functional groups
that exhibited activity. This iterative library process, coupled with
the binding screen, enabled rapid identification of lead compounds
for in vivo study. The intrinsic activity of the core lactam also pro-
vided evidence that the lactone was the active form of 5.
N-Alkyl and N-benzyl groups were investigated and the results
are displayed in Table 2. In summary, a clear trend was observed
for straight chain alkyl groups with the ideal chain length of 3–4
carbons being favored (12, 13). Branched alkyl chains containing
an
a-methyl substituent adjacent to the pantolactam ring (16,
17) were the most favored. Branching of the alkyl group further
away from the pantolactam ring resulted in less active compounds
(19, 20). A variety of alkyl ethers and thioethers were synthesized
and found to be only moderately active, with the most potent
being around 500 nM (21). Alkyl groups containing esters and
amides showed marginal activity generally. Only the methyl ester
provided moderate ARB activity (25). No other carbonyl containing
side chain lactam analogs exhibited appreciable ARB activity (not
shown). Simply changing the methyl ester to an ethyl ester led
to a seven fold decrease in binding activity (26). The benzyl analog
(28) was a particularly potent AR inhibitor.
The unsubstituted pantolactam was the starting point for diver-
sification with SAR developed through iterative library design. The
first iteration contained a wide variety of groups, such as alkyl
groups containing ethers, esters and amides, benzyl and heterocy-

5232
K. E. Sexton et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5230–5233
Table 3
Expanding on the activity of the benzyl analog (28), other ben-
SAR of racemic pantolactams based on 8
zyl aromatic and heteroaromatic groups were evaluated. Results
are displayed in Table 3. For simplicity, only monosubstituted ben-
zyl groups were synthesized in early iterations. The benzyl analog
and corresponding phenols, regardless of position on the ring, were
the most active of all benzyl substituted pantolactams (35–37). Of
the compounds containing 5 membered heterocycles, binding and
activity generally improved with added hydrophobic bulk (42–47).
Once a large variety of substituted pantolactams had been syn-
thesized and evaluated in the AR binding assay, they were then tri-
aged through additional assays which included the AR functional
assay (ARCELL), agonist activity (full vs. partial) and selectivity
against the progesterone receptor (PRB). A subset of 23 compounds
possessed the desired profile of an AR antagonist with good cellular
activity and selectivity against PRB. From this subset of com-
pounds, five were considered to possess suitable properties for top-
ical delivery: non-phototoxic, high clearance/rapid metabolism
and suitable solubility (data not shown). These five compounds
were separated into individual enantiomers by chiral chromatog-
raphy. The enantiopure compounds were evaluated for AR activity
and the results displayed in Table 4. As observed in the pantolac-
tone series (5), all AR antagonist activity was found in the (+)-iso-
mer for the pantolactams.
Additionally, we used molecular modeling to gain insights into
the binding mode of the pantolactams within the AR ligand bind-
ing domain (LBD). Consistent with our previous findings13, molec-
ular modeling of 50 in the crystal structure of the ligand- binding
domain of the androgen receptor indicated favorable interactions
in the W741L mutant LBD compared to that of the wild-type
(WT) LBD (Fig. 2). Compound 50 in the model binds in a similar
binding orientation as that of bicalutamide 3 with the terminal
benzyl group in 50 in a similar position and orientation like the
F-phenyl moiety in bicalutamide 3.5
Compound
R
ARB (nM)
ARCELL (nM)
29
30
31
32
33
34
35
36
37
38
39
40
41
2-OMe Bn
3-OMe Bn
4-OMe Bn
2-F Bn
3-F Bn
4-F Bn
2-OH Bn
3-OH Bn
4-OH Bn
4-SMe Bn
CH2-2-pyr
CH2-3-pyr
CH2-4-pyr
298
110
284
174
48
144
17
11
—
309
—
44
61
199
13
>600
32
51
—
17
187
767
880
128
—
>600
*
O
42
166
97
CO2Et
S
*
43
215
>900
N
CO2Me
S
*
*
44
45
43
51
—
N
S
324
N
N
O
*
*
46
47
84
40
54
N
Ph
O
N
159
N
Ph
Values (IC50) are given as an average of P2 experiments; —, not tested; ARB, human
androgen receptor binding assay; ARCELL, human androgen receptor cellular
functional assay.
To determine if cellular activity translated to in vivo efficacy,
the enantiopure compounds [(+) isomers] from Table 4 were tested
in the Golden Syrian Hamster Ear Model to evaluate their ability to
reduce wax and cholesterol esters. Wax and cholesterol esters con-
stitute 28% of total human sebum19 and, in a clinical trial with oral
cyproterone acetate, a direct correlation existed between reduction
in wax esters and reduction in total sebum production.20 The Ham-
ster Ear Model is a widely used animal model to test drug effects
on sebaceous glands.21
The in vivo results are summarized in Table 5. The selected
compounds were applied topically at the specified dose (%). The
% reductions in wax esters for the compounds are comparable to
a 1% formulation of the positive control, RU-58841 (4), which re-
duced wax esters by 95%. Due to the efficacy observed, compounds
48 and 50 were selected for further preclinical investigation.16
In summary, a series of pantolactam AR antagonists were iden-
tified using iterative library design. Using 50 as substrate, we
Table 4
Comparison of racemic and enantiopure pantolactams
Compound
R
Isomer
ARB (nM)
ARCELL (nM)
12
48
13
49
28
50
32
51
38
52
nPr
nPr
nBu
nBu
Bn
Bn
2-F Bn
2-F Bn
4-SMe Bn
4-SMe Bn
( )
(+)
( )
(+)
( )
(+)
( )
(+)
( )
(+)
188
225
119
91
26
83
16
10
12
38
44
92
51
28
30
100
174
112
187
316
Values (IC50) are given as an average of P2 experiments; —, not tested; ARB, human
androgen receptor binding assay; ARCELL, human androgen receptor cellular
functional assay.
Figure 2. Model of 50 (yellow ball and stick) in WT AR LBD (green-left) and W741L mutant AR LBD (orange-right) indicating favorable interactions with Arg752, Gln711.
W741L mutant structure relieves clashes with Trp-741 observed in WT. Bicalutamide ligand, 3, (white stick) is shown as reference.

K. E. Sexton et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5230–5233
9. Bernard, E.; Dubois, J.; Wepierre, J. J. Pharm. Sci. 1997, 86, 573.
5233
Table 5
10. Van Camp, J. A.; Hu, L.-Y.; Kostlan, C.; Lefker, B.; Li, J.; Mitchell, L.; Wang, Z.;
Yue, W.-S.; Carroll, M.; Dettling, D.; Du, D.; Pocalyko, D.; Wade, K. Bioorg. Med.
Chem. Lett. 2007, 17, 5529.
Cholesterol and wax ester reductions of enantiopure compounds
Compound
R
Dose (%) CE reduction (%) WE reduction (%)
11. Hu, L.-Y.; Lei, H. J.; Du, D.; Johnson, T. R.; Fedij, V.; Kostlan, C.; Yue, W. S.;
Lovdahl, M.; Li, J. J.; Carroll, M.; Dettling, D.; Asbill, J.; Fan, C.; Wade, K.;
Pocalyko, D.; Lapham, K.; Yalamanchili, R.; Samas, B.; Vrieze, D.; Ciotti, S.;
Krieger-Burke, T.; Sliskovic, D.; Welgus, H. Bioorg. Med. Chem. Lett. 2007, 17,
5693.
12. Hu, L.-Y.; Du, D.; Hoffman, J.; Smith, Y.; Fedij, V.; Kostlan, C.; Johnson, T. R.;
Huang, Y.; Kesten, S.; Harter, W.; Yue, W.-S.; Li, J. J.; Barvian, N.; Mitchell, L.; Lei,
H. J.; Lefker, B.; Carroll, M.; Dettling, D.; Krieger-Burke, T.; Samas, B.;
Yalamanchili, R.; Lapham, K.; Pocalyko, D.; Sliskovic, D.; Ciotti, S.; Stoller, B.;
Hena, M. A.; Ding, Q.; Maiti, S. N.; Stier, M.; Welgus, H. Bioorg. Med. Chem. Lett.
2007, 17, 5983.
48
49
50
51
52
(+)-nPr
(+)-nBu
(+)-Bn
(+)-2-F Bn
(+)-4-SMe Bn 1.5
1
2
3
3
76
66
68
70
75
85
83
83
86
89
Values are given as an average of P2 experiments; CE = cholesterol esters;
WE = wax esters.
13. Li, J. J.; Iula, D. M.; Nguyen, M. N.; Hu, L.-Y.; Dettling, D.; Johnson, T. R.; Du, D.
Y.; Shanmugasundaram, V.; Van Camp, J. A.; Wang, Z.; Harter, W. G.; Yue, W.-
S.; Boys, M. L.; Wade, K. J.; Drummond, E. M.; Samas, B. M.; Lefker, B. A.; Hoge,
G. S.; Lovdahl, M. J.; Asbill, J.; Carroll, M.; Meade, M. A.; Ciotti, S. M.; Krieger-
Burke, T. J. Med. Chem. 2008, 51, 7010.
14. Mitchell, L.; Wang, Z.; Hu, L.-Y.; Kostlan, C.; Carroll, M.; Dettling, D.; Du, D.;
Pocalyko, D.; Wade, K. Bioorg. Med. Chem. Lett. 2009, 19, 1310.
15. Mitchell, L.; Hu, L.-Y.; Nguyen, M.; Fakhoury, S.; Smith, Y.; Iula, D.; Kostlan, C.;
Carroll, M.; Dettling, D.; Du, D.; Pocalyko, D.; Wade, K.; Lefker, B. Bioorg. Med.
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identified potent antagonists that were more stable than the lead
lactone 5. Compounds of this structural type were able to reduce
sebum production in a validated animal model. Two compounds,
48 and 50, have been selected for additional preclinical studies
and will be the topic of future publications.
References and notes
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