Design, synthesis, and biological evaluation of 16-substituted 4-azasteroids as tissue-Selective Androgen Receptor Modulators (SARMs)

Article abstract of DOI:10.1021/jm900880r

A novel series of 16-substituted-4-azasteroids has been identified as potential tissue-selective androgen receptor modulators. These ligands display potenthARbinding and agonist activity, low virilizing potential, and good pharmacokinetic profiles in dogs

Full text of DOI:10.1021/jm900880r

4578 J. Med. Chem. 2009, 52, 4578–4581
DOI: 10.1021/jm900880r
on bone and muscle with reduced undesired andronizing
effects on tissues, such as the prostate and skin, for the
treatment of sarcopenia and osteoporosis.
Design, Synthesis, and Biological Evaluation of
16-Substituted 4-Azasteroids as Tissue-Selective
Androgen Receptor Modulators (SARMs)
From our previous work on the 5-R reductase program, we
have identified2, a4-aza analogue of1, asa fullagonistfor AR
with reduced androgenizing or virilizing potential compared
tothe full androgen agonistDHT. Inaddition to moderate5-R
reductase activity (41% inhibition at 1000 nM), the in vitro
profile of 2 is characterized by high binding affinity for human
AR (hAR) (IC50=7 nM) in the competitive AR binding assay
(ARBIND)5a and potent agonist activity (EC50=5 nM) in the
transactivation assay of hAR (TAMAR),5b a cell-based trans-
activation assay that examines potential to stimulate bone
formation. In the virilization assay (VIRCON),6 a two-hybrid
assay designed to measure virilizing potential, 2 displayed low
agonist activity (4%) in contrast to the full agonist DHT
(73%). The N-methyl group has a pronounced effect on the
ARBIND affinity, as the compound that lacks this moiety has
ARBIND IC50>1000 nM. The pharmacokinetic (PK) profile
of 2 in dogs is typified by a short plasma half-life (t1/2=42 min)
and a high clearance (CL) rate (32.3 (mL/min)/kg). An initial
set of N-methyl-4-aza steroids7 was evaluated for stability in
the presence of female rat, male rat, dog, and human liver
microsomes, and in general, there was good correlation
between the observed t1/2 in dog and human liver microsomes.
Moderate stability was observed in the presence of female rat
microsomes; however, high CL was generally observed in the
presence of male rat microsomes because of species specific
oxidation of the N-methyl group in male rats. Compounds
with appropriate in vitro and PK profiles are studied in vivo in
a female overiectimized (OVX) rat model for evaluation of
osteoanabolism and tissue selectivity.7 Compounds that
demonstrate selectivity in the OVX rat model are then studied
in the orchiectimized (ORX) male rat model to evaluate effects
on ventral prostate (VP) and seminal vesicles (SV). For this
initial class of compounds, we targeted a series of compounds
that maintained partial to full agonist activity in TAMAR
with minimal activity in VIRCON and improved PK based on
the structure of 2 and a series of 16-substituted-4-azasteroids
was investigated.
16-Alkyl and 16-alkenyl analogues were prepared by the
synthetic sequences shown in Scheme 1. The A-ring of testos-
terone 4 was oxidatively cleaved with potassium permanga-
nate8 to give keto acid 5. Conversion to the lactam was
facilitated by treatment with methylamine9 in ethylene glycol
at 180 °C, followed by platinum-catalyzed hydrogenation of
the 5,6-olefin to afford intermediate 6. The 1,2-olefin was
installed by a four-step, two-pot procedure involving silyla-
tion of the 17-alcohol with TESOTf and 2,6-lutidine, alkyla-
tion of the 2-position with phenylmethylsulfinate10 and KH to
afford the sulfoxide, thermal elimination in refluxing toluene,
and desilylation via treatment with HF in MeCN to afford
1,2-ene 7. Swern oxidation11 of the 17-alcohol afforded ketone
8, which was subsequently treated via one of two sequences.
For 16-alkyl substitution, ketone 8 was deprotonated with
LDA at-78°C and then treated withthe requisite alkylhalide
at -20 °C to afford ketone 9. Reduction of the ketone with
LAH (or NaBH4) at low temperature afforded the targeted
alcohols 10-12 in reasonable overall yields. For 16-alkenyl
Helen J. Mitchell,*,† William P. Dankulich,†
George D. Hartman,† Thomayant Prueksaritanont,§
Azriel Schmidt,‡ Robert L. Vogel,‡ Chang Bai,‡
Sheila McElwee-Witmer,‡ Hai Z. Zhang,‡ Fang Chen,‡
Chih-Tai Leu,‡ Donald B. Kimmel,‡ William J. Ray,‡
Pascale Nantermet,‡ Michael A. Gentile,‡
Mark E. Duggan,†,# and Robert S. Meissner†
†Department of Medicinal Chemistry, ‡Department of Molecular
Endocrinology, and §Department of Drug Metabolism,
Merck Research Laboratories, P.O. Box 4, 770 Sumneytown Pike,
#
West Point, Pennsylvania 19486. Current affliliation:
Link Medicine Corporation.
Received June 16, 2009
Abstract: A novel series of 16-substituted-4-azasteroids has been
identified as potential tissue-selective androgen receptor modula-
tors. These ligands display potent hAR binding and agonist activity,
low virilizing potential, and good pharmacokinetic profiles in dogs.
On the basis of its in vitro profile, 21 was evaluated in the OVX and
ORX rat models and exhibited an osteoanabolic, tissue-selective
profile.
The androgen receptor1 (ARa) is a member of the nuclear
receptor superfamily and is responsible for mediating the
physiological action of endogenous androgen ligands includ-
ing dihydrotestosterone (DHT, 1, Figure 1) and testosterone
(4).2 The AR is expressed in numerous tissues, and the
recruitment of cofactors and subsequent ligand-mediated
gene transcription results in the regulation of several physio-
logical characteristics including bone formation, muscle mass,
hair growth, acne, and sexual development. Androgen ther-
apy has been used in the clinic to treat a variety of male
disorders, including reproductive disorders and primary or
secondary hypogonadism. Patientswithandrogendeficiencies
often receive testosterone as a patch or gel because of its poor
oral bioavailability. Side effects include hair loss, gynecomas-
tia, and prostate hyperplasia.3 A number of natural and
synthetic AR agonists have been clinically investigated for
the treatment of musculoskeletal disorders, including sarco-
penia, which is characterized by a slow, progressive loss of
muscle mass occurring with advancing age. In addition, the
beneficial effects of combined estrogen/androgen therapy
versus estrogen therapy alone on bone in women with post-
menopausal osteoporosis have been documented.4 This evi-
dence provides strong rationale for our objective which is the
development of a tissue-selective AR agonist that is anabolic
*To whom correspondence should be addressed. Phone: (215) 652-
3007. Fax: (215) 652-7310. E-mail: Helen_mitchell2@merck.com.
aAbbreviations: AR, androgen receptor; DHT, dihydrotestosterone;
hAR, human androgen receptor; OVX, overiectimized; ORX, orchiec-
timized; ARBIND, androgen receptor binding assay; TAMAR, trans-
activation assay of endogenous human AR; VIRCON, virilization
assay; hERG, human ether-a-go-go-related gene; SV, seminal vesicle;
VP, ventral prostrate; UW, uterine weight; PK, pharmacokinetics; t1/2
half-life; CL, clearance; BFR, bone formation rate; SC, subcutaneous.
,
r
pubs.acs.org/jmc
Published on Web 07/16/2009
2009 American Chemical Society

Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4579
analogue 14 displayed partial agonist activity in the TAMAR
assay (EC50 = 12 nM, EMAX of 65%), minimal agonist
activity in the VIRCON assay (1%), and potent undesirable
hERG affinity (KI=29 nM). The addition of a second fluoro
substituent to afford 15 restored full agonist activity in
the TAMAR assay (EMAX=98%) and further improved
dog PK (t1/2 =9.1 h; CL=6.8 (mL/min)/kg); however, no
improvement was observed in the hERG affinity (KI =
46 nM). Removal of the substituents to afford styrene 16
maintained full agonist activity but only afforded a modest
improvement in the hERG affinity (KI=225 nM). Further
truncation to afford ethylene analogue 17 again main-
tained full agonist activity and reduced hERG affinity (KI=
8050 nM) but resulted in poor dog PK with a short t1/2 (1.0 h)
and high CL (42.8 (mL/min)/kg).
Figure 1. Structure of AR leads.
Scheme 1. Synthesis of AR ligands.
To address the undesirable hERG activity and restore the
improved PK observed with the styrenyl analogues, the more
basic pyridine and pyrimidine analogues 18-26 were identi-
fied and evaluated. A general potency trend in ARBIND was
observed for the pyridyl analogues in that 3-pyridyl 20 was
more potent than 4-pyridyl 19, which was more potent than
2-pyridyl analogue 18, with ARBind IC50 values of 62, 129,
and 292 nM, respectively. The 4-pyridyl analogue 19 exhi-
bited partial agonist activity in TAMAR (EC50 = 138 nM,
EMAX=69%) with low VIRCON activity; however, hERG
affinity was not improved. The 3-pyridyl 20 restored full
agonist activity in TAMAR, maintained low VIRCON activ-
ity (3%), and had reduced hERG affinity (KI=3600 nM)
and improved dog PK (t1/2=17.1 h, CL=5.0 (mL/min)/kg,
and 21% oral bioavailability). It was also observed that the
addition of a second nitrogen to the aryl ring, i.e., on moving
from pyridine 20 to pyrimidine 21, afforded at least a 3-fold
increase in TAMAR agonist potency; i.e., 3-pyridyl 20 had an
EC50 of 62 nM, whereas pyrimidines 21 and 24 (which differ in
structure by only one methyl group) had TAMAR EC50
values of 17 and 8 nM, respectively, while maintaining the
full agonist activity in TAMAR. The unsubstituted pyrimi-
dine 21 displayed low agonist activity in VIRCON (6%), a t1/2
of 2.3 h, and a CL rate of 15.3 (mL/min)/kg. When dosed
orally from an aqueous 0.5% methylcellulose suspension to
dogs, 21 afforded 51% bioavailability. The addition of sub-
stituents to the 2-position of the pyrimidine structure resulted
insignificant changes in theseparametersincludingsignificant
increases in VIRCON activity, increased TAMAR potency,
and improved PK in dogs. Both alkyl (22, 24) and polar
(23, 25) substituents were tolerated; however, larger substitu-
ents such as a 2-[2-pyridyl] analogue 26 were not tolerated and
resulted in a loss of binding activity. These changes are
typified by the methylpyrimidine 24, a potent full agonist in
TAMAR (EC50 = 8 nM, EMAX = 137%), high agonist
activity in VIRCON (82%), a longer t1/2 of 18.7 h, and a
lower CL (1.5 (mL/min)/kg) in dogs. This methyl group also
resulted in a lower water solubility for 24 (0.23 mg/mL at
pH 2) than for 21 (0.57 mg/mL at pH 2); however, both were
still reasonable. Importantly, all pyrimidine analogues 21-25
had significantly weaker hERG activity with KI between 4650
and 22 500 nM. Compounds 21 and 24 exhibited good
selectivity against other nuclear receptors including glucocor-
ticoid, mineralocorticoid, progesterone, and estrogen recep-
tors (IC50 >1000 nM), and the addition of the 16-olefin
resulted in a loss of the 5-R reductase activity.
substitution, ketone 8 was treated with the appropriate alde-
hyde and KOH in ethanol to afford trans-enone12 13, which
was also reduced with LAH at low temperature to afford
styrenyl analogues 14-26.
A series of compounds were designed and synthesized
and their in vitro profiles evaluated with the aim of optimiz-
ing agonist potency, minimizing virilizing potential, and
improving t1/2 in dogs. Compounds with sufficient affinity
in ARBIND (IC50<200 nM) were tested in the TAMAR and
VIRCON assays, counterscreened for human ether-a-go-go-
related gene (hERG) Kþ ion channel13 affinity to assess a
compound’s ability to affect heart through QT prolongation,
and then evaluated for PK in beagle dogs.
A series of 16-alkylated analogues (10-12; see Table 1)
displayed only 3- to 5-fold weaker binding affinity than lead 2;
however, methyl and methoxymethyl analogues 10 and 11
exhibited a significant loss of agonist activity and potency in
TAMAR with EC50 values of 119 and 612 nM and EMAX
values of 54% and 43%, respectively. In contrast, 3-fluoro-
benzyl analogue 12 maintained potency and partial agonist
activity in TAMAR (EC50=14 nM, EMAX=40%) while at
the same time exhibiting minimal agonist activity in the
VIRCON assay (1%). In addition, when 12 was evaluated
for dog PK, it displayed a modest increase in t1/2 (3 h) and
a lower CL (22.0 (mL/min)/kg) compared to the lead 2.
Styrenyl analogue 14, exhibited improved PK with a t1/2 of
4.9 h and a lower CL (15.2 (mL/min)/kg). The monofluoro
This subtle structural change that resulted in a significant
shift in virilizing potential and PK profile made analogues 21
and 24 attractive for further investigation. Thus, pyrimidines

4580 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15
Mitchell et al.
Table 1. Binding Affinity, Transcriptional Activities, and PK Data for Agonists 1, 2, 10-12, and 14-26
ARBind
IC50 (nM)
TAMAR EC50
(nM) (% EMAX)
VIRCON
% at 300 nM
hERG affinity
KI (nM)
dog iv
t1/2 (h)b
dog CL
((mL/min)/kg)b
dog F
(%)c
ligand
a
a
a
1
1
7
2 (100)
5 (105)
119 (54)
612 (43)
14 (40)
12 (65)
8 (98)
73
4
-
-
-
2
130000
20000
39000
240
0.7
1.0
1.5
3.0
4.9
9.1
32.3
20.2
11.0
22.0
15.2
6.8
10
11
12
14
15
16
17
18
19
20
21
22
23
24
25
26
31
24
23
27
41
116
35
292
129
62
59
51
11
43
31
715
<1
2
1
1
29
46
1
a
a
26 (140)
17 (92)
1
225
8050
-
1.0
-
42.8
1
a
-
a
a
a
a
-
-
-
-
a
a
138 (69)
62 (93)
17 (141)
26 (140)
2 (158)
8 (137)
5 (148)
1
320
3600
9400
4650
7900
15000
22500
-
17.1
-
5.0
3
21
51
6
2.3
a
15.3
a
-
50
79
82
87
-
12.7
18.7
10.9
4.6
1.5
0.8
a
-
a
a
a
a
-
-
-
-
a Not tested. b The iv injection of 0.2 mpk compound in DMSO to two male or female beagle dogs as PK cocktails. c The po administration of 1 mpk
compound in 0.5% aqueous methylcellulose to two male or female beagle dogs as single compounds.
Table 2. Normalized OVX Data for 21 and 24a
dose,
mpk
AUC,
μM h
BFR,b
% DHT
UW change,c
% DHT
skin effect,d
% DHT
ligand
3
DHT
21
24
3
10
1
0.02
17
17
100
120
113
100
7
100
6
65
61
a For complete details, refer to Supporting Information. b Assessed for
total periosteal surface, single fluorochrome label, double fluorochrome
label, interlabel distance, and a BFR is then calculated and reported as %
activity to DHT. c The uterus is located, blunt dissected free, blotted dry, and
weighed. d Skin QRT-PCR: Sections of skin are collected, RNA is extracted,
and two genes are amplified and quantified.
Figure 2. In vivo BFR and UW data for 21 in OVX rat.
uterus and the skin. Increase in uterine weight (UW) is
determined by measuring the isolated wet weight (vs vehicle
in blue; see Figures 2 and 3), and the data are reported as a %
of the effect caused by DHT (set to 100%; see Table 2). The
effect on skin is determined by removal of sections of
skin from the back of the rats, extraction of the RNA, and
amplification and quantification by quantitative real-time
RT-PCR analysis of two genes involved in sebum secretion.
The skin data are also reported as a % of the effect caused by
DHT (set to 100%). At an AUC of 17 μM h, the low
3
VIRCON pyrimidine 21 exhibited a BFR equal to that of
DHT (120%), with minimal effects on skin (6% of DHT) and
minimal change in UW (7% of DHT).
Figure 3. In vivo BFR and UW data for 24 in OVX rat.
In contrast, when dosed to achieve the same AUC, the high
VIRCON pyrimidine 24 exhibited a BFR equal to that of
DHT (113%) but also significant virilizing effects. Pyrimidine
24 caused a 65% increase in UW and a similar 61% effect on
skin compared to DHT. To confirm the attenuated virilizing
potential of 21, it was evaluated in male ORX rats by dosing sc
once daily for 17 days and then determining the change in VP
and SW weightscompared toDHT(set to100%) (see Figure4
and Table 3). Higher doses were required in the male ORX rat
model because of metabolism of the N-Me group; therefore, a
dose of 30 mpk was required to achieve an exposure similar to
21 and 24, in addition to DHT as a positive osteoanabolic and
virilization control, were evaluated in the bone formation
assay. In this assay, nine female Sprague-Dawley rats are
OVX, to cause bone loss and simulate estrogen deficient,
osteopenic adult human females. Following pretreatment
with a low dose of an antiresorptive,14 the rats are then dosed
with the test compounds subcutaneously (sc)15 once daily for
24 days. On the 5th and 15th days of treatment, a single sc
injection of calcein (8 mg/kg) is given (measures increase in
bone formation, shown by increased fluorochrome labeling at
the periosteal surface of the femur). The osteanabolic effect
(versus vehicle in blue; see Figures 2 and 3) is calculated from
these data and is reported as a bone formation rate (BFR) as a
% of the effect of DHT (set to 100%) at a standard dose (see
Table 2). Virilizing effects are evaluated in two organs: the
thatobtained inthe OVX model. At16.2μM h, 21exhibited a
3
3% increase in VP weight and a 21% increase in SV weight
compared to DHT, confirming its tissue selectivity.
In summary, we have identified a novel series of 16-sub-
stituted 4-azasteroids as potent and selective AR modulators.

Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4581
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Figure 4. In vivo VP and SV wt data for 21 in ORX rat.
Table 3. Normalized ORX Data for 21a
dose,
mpk
AUC,
μM h
VP wt change,b
% DHT
SW wt change,c
% DHT
ligand
3
DHT
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21
3
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30
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100
8
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21
a See Supporting Information for complete details. Six male Sprague-
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day 17. b VP is located, blunt dissected free, blotted dry, and weighed. c SV is
located, dissected free, blotted dry, and weighed.
(5) Refer to Supporting Information. (a) Characterized by the dis-
placement of [3H]methyltrienolone by compounds in the hAR from
MDA-MB-453 cells. (b) Measured by the ability of test compounds
to control transcription from the MMTV-LUC reporter gene in
MDA-MB-453 cells. (c) Quantified by the ability of agonists to
induce stable assembly of an AR N-terminal /C-terminal interac-
tion. Values are % of agonism of R1881.
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and observed in vivo effects are the subject of a separate manu-
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in VIRCON, reduced affinity for the hERG Kþ channel, and
good dog PK. In addition, this work demonstrated that a
good in vitro/in vivo correlation between potency in TAMAR
and BFR and the percent agonism in the VIRCON assay and
the effects observed on the skin and uterus in OVX rats exists
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Supporting Information Available: Experimental procedures
and characterization data of final compounds and details for the
biological evaluation of compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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resorptive agent was used to suppress bone resorption in order to
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(15) Other administration routes were also used. Compound 24 gave
similar in vivo effects when dosed orally from a 0.5% aqueous
methylcellulose suspension.