Rational design of a topical androgen receptor antagonist for the suppression of sebum production with properties suitable for follicular delivery

Article abstract of DOI:10.1021/jm9018004

A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4- dimethyl-2-oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound, which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model, was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.

Full text of DOI:10.1021/jm9018004

4422 J. Med. Chem. 2010, 53, 4422–4427
DOI: 10.1021/jm9018004
Rational Design of a Topical Androgen Receptor Antagonist for the Suppression of Sebum Production
with Properties Suitable for Follicular Delivery
Lorna H. Mitchell,*,† Theodore R. Johnson,^,3 Guang Wei Lu, ,O Daniel Du,‡ Kaushik Datta,# Felicity Grzemski,#,O
Veerabahu Shanmugasundaram,†,O Julie Spence, Kim Wade,‡,[ Zhi Wang,† Kevin Sun,† Kristin Lin,† Lain-Yen Hu,†
Karen Sexton,† Neil Raheja,† Catherine Kostlan,† and David Pocalyko‡
†Department of Chemistry, ‡Department of Dermatology Biology, Department of Pharmaceutical Sciences, ^Department of Pharmacokinetics
Dynamics and Metabolism, #Department of Drug Safety Research and Development, and Michigan Laboratories, Pfizer Global Research & Development,
2800 Plymouth Road, Ann Arbor, Michigan 48105. 3Present address: Pfizer Global Research and Development, 10777 Science Center Drive, San Diego,
California 92121. OPresent address: Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340. [Present address:
Pfizer Global Research and Development, 800 North Lindbergh, Creve Coeur, Missouri 63141.
Received February 12, 2010
A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yloxy)-
2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound,
which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model,
was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.
Introduction
The androgen receptor (ARa), a ligand-activated nuclear
hormone receptor, is responsible for the activation of genes
involved in the pathogenesis of acne and alopecia.1 The onset
of acne vulgaris infections in the pilosebaceous unit is asso-
ciated with excess sebum production. The production of
Figure 1. Structures of 1 and RU-58841 (2).
sebum is regulated by androgens such as testosterone and
5R-dihydrotestosterone (5R-DHT), and higher levels of these
androgens cause the sebaceous glands to become larger and
produce more sebum, an effect that can be blocked with AR
antagonists (antiandrogens). Extensive research in the last
two decades has delivered many examples of nonsteriodal
antiandrogens.2 It has been shown that cyproterone acetate3
and spironolactone,4 used as oral contraceptives in women,
significantly reduce sebum production and decrease the se-
verity of acne. However, oral administration of AR antago-
nists for the treatment of acne and oily skin is undesirable due
to the potential for systemically driven adverse antiandrogen-
mediated side effects. Precedence for topical delivery of anti-
androgens to the pilosebaceous unit has been reported with
RU-58841 (2) (Figure 1), which suppresses sebum production
when applied topically in an animal model.5 We have also
previously reported topically delivered nonsteroidal benzoni-
trile antiandrogens with efficacy in a validated animal model,
which were designed to exhibit antiandrogen activity locally,
in the pilosebaceous unit, yet be rapidly cleared upon reaching
the systemic circulation.6
Topically applied agents can reach the pilosebaceous unit by
either the transepidermal route or the transfollicular (follicular)
route, and both pathways occur simultaneously in most cases.
The relative contribution to drug delivery through each path-
way varies depending on the nature of the formulation and the
physicochemical properties of the drug. Drug delivered by the
transepidermal route involves distribution into the pilosebaceous
unit secondary to absorption into other local skin substructures
and the systemic circulation via the dermal capillary bed, so
there is potential for adverse side effects due to systemic anti-
androgen exposure. Follicular delivery, on the other hand, offers
direct access to the pilosebaceous unit without systemic expo-
sure. Targeted follicular delivery of topically applied drugs has
increasingly been recognized as an efficient method to enhance
local efficacy and reduce systemic exposure.7 Increased delivery
by the follicular route can be achieved by either modification of
the formulation8 or, less commonly, by modification of the
physicochemical properties of the drug molecule itself.9 In the
current work, we describe an approach in which we modified the
physicochemical properties of our previously reported benzoni-
trile series of AR antagonists to give compound 1 which we
propose is delivered preferentially by the follicular route.
*To whom correspondence should be addressed. Phone: þ44 1304
649599. Email: lorna.h.mitchell@gmail.com. Present address: Medicinal
Chemistry Department, Sandwich Laboratories, Pfizer Global Research &
Development, Ramsgate Road, Sandwich CT13 9NJ, UK.
In Vitro Activity and Chemistry
a Abbreviations: AR, androgen receptor; 5R-DHT, 5R-dihydrotestos-
terone; Ro5, rule-of-five; ARB, androgen receptor binding; ARCELL,
androgen receptor cellular activity; PRB, progesterone receptor binding:
PR, progesterone receptor; WE, wax esters; CE, cholesterol esters; IVT, in
vivo toleration; CL, clearance; BID, twice a day dosing; EH, extraction
ratio; PEG, polyethylene glycol, SEM, standard error of the mean.
We have previously reported benzonitriles, such as 3, 4, and
5 as AR antagonists for the topical control of sebum produc-
tion and/or androgenetic alopecia (Figure 2).6 These com-
pounds were designed to occupy the physicochemical
property space defined by the Rule-of-Five (Ro5),10 which
r
pubs.acs.org/jmc
Published on Web 05/12/2010
2010 American Chemical Society

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11 4423
was derived from an analysis of oral drugs. Modification of
compound size, lipophilicity, and polar surface area to prop-
erty space outside of Ro5 compliance can give increased
delivery via the follicular route.9
reduce wax esters (WE) and cholesterol esters (CE), which are
biomarkers for sebum production (Table 1).16 Compounds 1
and 9 emerged from this evaluation as the lead compounds
(Figure 4). However, it was found that sulfide 9 was converted
into active metabolites, the sulfones, with long half-lives, so 1
was the compound selected for further characterization of
properties predictive for enhanced follicular delivery.
Compound lipophilicity is a particularly important property
to consider with regard to designing compounds with increased
propensity for distribution into the sebum-rich hair follicle.
Compound flux through skin is correlated in a parabolic rela-
tionship with lipophilicity, while compound partitioning into
sebum increases with increasing lipophilicity (Figure 3).11 In-
creased partitioning into sebum and decreased skin flux are both
indicators that can be used to suggest increased follicular delivery
if evidence is also present that drug has reached the site of action
(for example, efficacy in an animal model of sebum control).
We designed and synthesized 540 analogues in the benzoni-
trile series through targeted libraries and singleton chemistry
with cLogP values greater than four (rather than 3 as shown in
Figure 3 because we had observed an order of magnitude
difference between calculated and measured LogP values for
existing compounds) and evaluated them for activity in an AR
binding (ARB)12 and cellular assay (ARCELL).13 We found
that we had a narrow window of increased lipophilicity in which
to operate because the percentage of compounds showing good
activity in the cellular assay decreased dramatically with in-
creased lipophilicity, presumably due to a decrease in cellular
permeability. Potent compounds were further evaluated for
their ability to partition into artificial sebum.14 All compounds
were also screened through a progesterone receptor binding
assay (PRB)15 because the PR is the nuclear hormone receptor
with highest homology at the ligand-binding region to the AR
(80-90%). Compounds with good in vitro profiles were then
tested in vivo in golden Syrian hamsters for their ability to
Compound 1 binds to the human AR17 with an IC50=100
nM and is 44-fold selective versus binding at the PR. This level
of selectivity is not anticipated to be problematic because the PR
does not have a significant function in skin tissue, so local der-
mal side effects are unlikely. The compound was designed to be
rapidly cleared with very low anticipated systemic exposure at
the projected efficacious human dose, so it is unlikely that sys-
temic side effects will emerge. Compound 1 is more than 100-
fold selective for the AR compared to various other nuclear hor-
mone receptor binding assays (IC50 > 10 μM in binding assays
of glucocorticoid, estrogen, and thyroid hormone receptors).
In the AR cellular assay, compound 1 was a full AR antago-
nist with an IC50 =38 nM. Because our in vivo studies were
carried out in hamsters, we also evaluated binding of 1 against
the hamster AR (IC50=27 nM) and in a hamster cellular assay
(IC50=104 nM). The AR binding and cellular activities of the
more lipophilic compound 1 are comparable to that seen for the
previous benzonitrile compounds designed for transepidermal
delivery.6
Our previously reported approach to the synthesis of
pantolactam benzonitriles like 1 and 9 was not suitable for
scale-up because it was lengthy due to a protection-deprotec-
tion sequence and it suffered from loss of >50% of the
material in a final chiral chromatography step.18 To supply
sufficient quantities of compound 1 for efficacy, safety, and
formulation studies, a new short high-yielding route was
developed in which the chiral center was purchased cheaply
in the form of (R)-pantolactone (Scheme 1).19
In Vivo Activity
Wax and cholesterol esters constitute 28% of total human
sebum,20 and it has been shown that there is a direct correla-
tion between reduction in WE and reduction in total sebum
Figure 2. Structures of previous AR antagonists designed for
transepidermal topical delivery.
Figure 3. Relationship between lipophilicity, sebum partitioning,
and skin flux.
Figure 4. Example structures of compounds designed with in-
creased lipophilicity.
Table 1. Example SAR of Compounds Designed with Increased Lipophilicity
ARBa (nM)
ARCELLa (nM)
PRBa (nM)
logKsebum
%CEc reduction
%WEc reduction
b
compd
cLogP
1
4.70
4.64
4.84
5.11
5.26
100
488
174
184
316
38
60
44
54
28
4400
>10000
4820
3.92
4.06
3.95
4.48
4.6
61
24
42
50
75
78
31
72
64
89
6
7
8
9d
6950
>10000
a Values (IC50) are given as an average of g2 experiments. b Partitioning into artificial human sebum. c All compounds were tested in vivo at a 1% dose
unless otherwise stated. d Tested in vivo at a 1.5% dose.

4424 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11
Mitchell et al.
Figure 6. Reduction of WE induced by compound 1 correlates with
the reduction of sebaceous gland size in the hamster ear model.
Figure 5. Dose-dependent reduction of sebum production, as
measured by the reduction of WE, in the hamster model following
2 weeks BID application of 1 in a vehicle of PEG 400:water:ethanol
(25:25:50, w/v).
Figure 7. Reduction of WE induced by compound 1 is fully reversible.
Scheme 1. Synthetic Route to Lactams 1 and 9 Developed to
Supply Bulk Compounda
Note: The reversibility was studied after the animals were treated BID for
2 weeks with 0.2% of 1 in a vehicle of ethanol:propylene glycol:transcutol
(60/20/20, v/v). Mean ( SEM was shown in the figure (N = 5).
is significantly lower than that of the compounds we had
previously designed for topical delivery by the tranepidermal
route, suggesting that drug has reached the site of action (the
pilosebaceous unit) by increased follicular delivery.
a Reagents and conditions: (a) R-benzylamine, toluene, 70 ꢀC (R=H,
87%; R=SMe, 95%); (b) MsCl, Et3N, NaHMDS (R = H, 61%; R=SMe,
76%); (c) 4-fluoro-2-(trifluoromethyl)benzonitrile, K3PO4, NaOH (R=H,
72%; R=SMe, 94%).
Sebum Partitioning. Compound 1 shows increased parti-
tioning into sebum compared to the previous compounds,
suggesting that it should favor the sebum-rich follicle. The
partition coefficient between sebum and water was deter-
mined by equilibrating ∼5 mg of drug spiked sebum sample
(1 mg/250 μL sebum) with 1 mL of saturated aqueous
solution at 37 ꢀC for 15 h and analyzing the drug concentra-
tion in the aqueous samples. Compound 1 has the highest
sebum partition coefficient when compared to previously
evaluated AR antagonists (Table 2), indicating a potential
advantage for sebaceous gland-targeted follicular delivery.
Skin Flux. In vitro penetration of 1 through human
cadaver skin was evaluated in order to quantify the delivery
properties of the compound and formulation. These data
were used to select an appropriate formulation for phase 1
studies and to provide necessary information for human
exposure projections.
production in a clinical trial with oral cyproterone acetate.21
The hamster ear model, a widely used animal model to test
drug effects on sebaceous glands, was used to evaluate 1.16
Compound 1 is a potent inhibitor of WE production in the
hamster ear model with an ED50 = 0.2% (0.02 mg/cm2, BID
application for 2 weeks) tested in the vehicle selected for phase
1 studies. The dose-response relationship of 1 is shown in
Figure 5 (mean ( SEM, N = 5).
Wax ester reduction caused by 1 correlated well with reduced
sebaceous gland size as quantified by fatty acid synthase im-
munohistochemical staining (Figure 6) (correlation coefficient=
0.972). The reduction in sebaceous gland size was not associated
with histopathological evidence of cytotoxic changes in sebocytes
after 2 weeks of BID application. The reduction of sebaceous
gland size and WE production were fully reversible after 2 weeks
BID application of 1 (Figure 7, mean ( SEM, N = 5).
The delivery of 1 through skin from various vehicles was
evaluated in human cadaver skin using a Franz Cell system.
The amount of tritiated-1 penetrating through the skin into
receptor solution was measured at various time points up to
48 h, and drug levels in the epidermis and dermis were
Evidence for Follicular Delivery
Compound 1 retains efficacy in the in vivo model even
though transepidermal flux, in both human and hamster skin,

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11 4425
Table 2. Comparison of Sebum-Water and Octanol-Buffer Partition
Coefficients of 1 with Previous Compounds
species allometric scaling24 of unbound CL in rat predictshigh
CL for 1 in humans (CLb = 16 mL/min/kg, EH = 0.80).25
Collectively, these results suggest that delivery of efficacious
concentrations to the target site of action can be achieved and
that the fraction of drug reaching the systemic circulation is
likely to be cleared rapidly, thereby minimizing unwanted
systemic effects.
parameter
1
3
4
5
logKsebuma human (artificial)
logKsebuma hamster
ElogD7.4
3.92
3.85
4.88
2.06
b
3.03
b
2.74
b
3.73
3.40
3.33
a Sebum-water partition coefficient. b not determined.
We proceeded to investigate the safety profile of compound
1. It showed no evidence of skin sensitization in a murine local
lymph node contact hypersensitivity assay.26 In an in vivo
tolerance (IVT) assessment in minipigs, 1 applied topically
exhibited good dermal toleration and minimal systemic anti-
androgen effects.27 An oral IVT study was also carried out in
rats and no systemic antiandrogen effects were observed when
compound 1 was dosed at 40-fold the anticipated human
exposure of projected efficacious dose.28
Table 3. Comparison of Skin Flux of Compounds 1 and 4 Using
Various Skin Samples
skin flux (μg/cm2/h)a
compd
hamster ear
human
1
4
0.060 ( 0.030
0.878 ( 0.149
0.005 ( 0.003
0.081 ( 0.032
a Data from multiple donor studies (mean ( SD). Studies were carried
out using the phase I vehicle selected for each compound: compound 1,
PEG 400:water:ethanol (25:25:50, w/v); compound 4, propylene glycol:
ethanol (30:70 w/v).
Summary
We have designed and synthesized a novel nonsteriodal AR
antagonist, 1, for the topical suppression of sebum produc-
tion. Compound 1 has sebum partitioning, skin flux, and in
vivo parameters that suggest it should be delivered preferen-
tially by the follicular route.
measured at 48 h. The average flux in the phase I vehicle,
PEG 400:water:ethanol (25:25:50, w/v), across three donors,
with n = 4, was 0.005 ( 0.003 μg/cm2/h. We compared the
skin flux of compounds 1 and 4 in their respective phase I
vehicles, in both human and hamster skin, in order to
determine if there was a difference in the properties of 1
compared to previously described compounds. Hamster ear
skin was separated from fresh ears immediately before the
study, and human cadaver skin was obtained from a com-
mercial supplier. As shown in Table 3, the flux of 1 and 4 was
approximately 10 times higher through hamster ear skin than
through human skin. The results also showed that the skin
flux of 1 was significantly lower than that of 4 in hamster ear
skin, demonstrating a similar reduction of skin flux of 1
versus 4 in skin samples from both species. Furthermore, as
the ED50 values in the hamster ear sebum model for these two
compounds are similar (0.2%), these data indicate that
efficacy of 1 in the hamster model is not directly dependent
on transepidermal delivery; it is more likely that delivery by
the follicular route is the primary route of delivery.
Experimental Section
General. All reagents and solvents were used as received from
commercial sources unless otherwise noted. All chemistry ex-
periments were conducted under an inert nitrogen atmosphere
1
unless otherwise noted. H NMR spectra were recorded on a
Varian 400 MHz nuclear magnetic resonance spectrometer or a
Bruker 400 MHz nuclear magnetic resonance spectrometer. 1H
NMR spectra were recorded in CDCl3 or DMSO-d6, and
chemical shifts are reported relative to the residual solvent peak.
The following abbreviations were used to assign spectra: s =
singlet, d = doublet, t = triplet, q = quartet, s = septet, m =
multiplet. Mass spectral analysis was conducted on a Waters
Micromass ZQ instrument. Elemental analysis was performed
at Quantitative Technologies, Inc., Whitehouse, NJ. The purity
of all final compounds was determined to be g95% by HPLC,
and all final compounds, with the exception of 9, which was a
gum so not tested, gave combustion analysis consistent with the
compound molecular formula. All data are available in the
Supporting Information.
Pharmacokinetics and Safety
Synthesis of Key Compound (R)-4-(1-benzyl-4,4-dimethyl-2-
oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)-benzonitrile (1). Ben-
zylamine (41.9 mL, 384 mmol) was added to a solution of (R)-
pantolactone (50.0 g, 384 mmol) intoluene (140 mL). The reaction
mixture was heated at 70 ꢀC for 7 h, and then hexane (10 mL) was
added. The solution was stood in the refrigerator overnight, and
the resulting precipitate was collected by filtration, washed with
cold hexane, and then allowed to dry to give (R)-N-benzyl-2,4-
dihydroxy-3,3-dimethylbutanamide (11) (79 g, 87% yield) as a
An ideal topical drug exerts its desired pharmacological
effect locally but then is rapidly inactivated by metabolism
once it reaches the systemic circulation. The pharmacokinetic-
ADME properties of 1 were evaluated and found to be con-
sistent both with this profile and with characteristics predic-
tive of selective follicular delivery. In addition to the enhanced
sebum partitioning and decreased transepidermal flux de-
scribed previously, delivery of 1 to the pharmacological site
of action was demonstrated in hamsters. Compound 1 was
readily absorbed into ear sebaceous glands of hamsters follow-
ing topical application.22 Maximal concentrations of 156 μM
of 1 were reached within 1 h of application of a 0.2% dose
and were maintained for 8 h postdose. Thereafter, compound
1 was eliminated from sebaceous glands, with an apparent
terminal half-life of ∼7 h. Furthermore, 1 was rapidly meta-
bolized in human liver microsomes,23 with intrinsic clearance
and predicted hepatic extraction ratio (EH) values of 121 mL/
min/kg and 0.85, respectively. Following intravenous admin-
istration of 1 to rats, mean blood clearance was 57 mL/min/
kg. This value is approximately 80% of hepatic blood flow,
indicating that 1 is a high clearance compound in rats. Single
1
white solid. MS(APCIþ): m/z 238. MS(APCI-): m/z 236. H
NMR (DMSO-d6) δ (ppm): 8.19 (br s, 1H), 7.25 (m, 5H), 5.40 (m,
1H), 4.44 (m, 1H), 4.22 (m, 2H), 3.78 (m, 1H), 3.20 (m, 2H), 0.80
(s, 3H), 0.78 (s, 3H).
A solution of (R)-N-benzyl-2,4-dihydroxy-3,3-dimethylbuta-
namide (11) (27.1 g, 114 mmol) in tetrahydrofuran (270 mL) and
triethylamine (17.5 mL, 125.5 mmol) was cooled in an ice/salt
bath and then a solution of methanesulfonyl chloride (8.9 mL,
114 mmol in 20 mL tetrahydrofuran) was added dropwise over
15 min. The reaction mixture was stirred for 30 min, and then it
was added by cannula to a solution of sodium bis(trimethyl-
silyl)amide (365 mL of a 1 M solution in tetrahydrofuran,
365 mmol) that was cooled in an ice/salt bath. The reaction
mixture was allowed to warm to room temperature with stirring

4426 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11
Mitchell et al.
overnight. Saturated ammonium chloride was added (100 mL),
and the tetrahydrofuran was removed on the rotovap. The
residue was extracted with ethyl acetate (2 ꢀ 150 mL), the
combined extracts were washed with saturated ammonium
chloride and then with 10% citric acid (2 ꢀ 150 mL), dried with
magnesium sulfate, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica eluting
with a ethyl acetate/heptane 0% to 70% gradient to give (R)-1-
benzyl-3-hydroxy-4,4-dimethylpyrrolidin-2-one (13) (15.2 g,
61% yield) as a pale-yellow oil. MS(APCIþ): m/z 220; 99.6%
by chiral HPLC. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.21 (m,
5H), 4.42 (dd, 2H), 3.98 (s, 1H), 2.87 (2d, 2H), 2.75 (d, 1H), 1.10
(s, 3H), 0.90 (s, 3H).
Potassium phosphate (14.7 g, 69.5 mmol) was added to a
solution of (R)-1-benzyl-3-hydroxy-4,4-dimethylpyrrolidin-2-
one (13) (15.2 g, 69.5 mmol) and 4-fluoro-2-trifluoromethyl-
benzonitrile (13.1 g, 69.5 mmol) in 75 mL of dimethylform-
amide, and then powdered sodium hydroxide (2.8 g, 69.5 mmol)
was added. The reaction mixture was stirred at room tempera-
ture for 1.5 h, and then water (200 mL) was added. Extracted
with ethyl acetate (2 ꢀ 200 mL), the combined extracts were
dried over magnesium sulfate and concentrated in vacuo to give
a white solid. The crude product was purified by flash chroma-
tography on silica eluting with a ethyl acetate/heptane 0% to
40% gradient to give (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrro-
lidin-3-yloxy)-2-(trifluoromethyl)-benzonitrile (1) 19.3 g, 72%
yield) as a white solid; 100% by LCMS, MS(APCIþ): m/z
389; 100% by HPLC: Chiralcel OD, 250 mm ꢀ 21 mm, 80/20
hexane:EtOH, 254 nM, flow rate = 0.8 mL/min, injection
volume=10 μL, retention time=8.43 min. 1H NMR (400 MHz,
CDCl3) δ (ppm): 7.75-7.20 (m, 8H), 4.60 (s, 1H), 4.48 (2d, 2H),
3.05 (s, 2H), 1.20 (s, 3H), 1.10 (s, 3H). Specific rotation
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(Rudolph Research analytical model AutoPol IV): [R]D
=
þ219ꢀ in chloroform. Anal. Calcd for C21H19F3N2O2, C,
64.94; H, 4.93; N, 7.21; F, 14.68. Found C, 65.08; H, 4.97; N,
7.23; F, 14.27%.
Supporting Information Available: Experimental conditions
for intermediates and final compounds; 1H NMR spectra,
LCMS and HPLC chromatograms; lipid analysis for hamster
ear samples; experimental conditions for androgen receptor
binding assay; androgen receptor cellular assay; male Syrian
hamster ear model for sebum reduction; pharmacokinetics on
topical application in hamster sebaceous glands; metabolic
stability in human liver microsomes; pharmacokinetics in rats
following intravenous administration; red blood cell distribu-
tion study conditions; local lymph node assay in BALB/c mice;
toxicity study in minipigs on topical application; toxicity study
in rats following oral dosing. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Supporting Information.