Discovery of a novel series of nonsteroidal androgen receptor modulators: 5- or 6-oxachrysen-2-ones

Article abstract of DOI:10.1016/j.bmcl.2008.03.085

A novel oxachrysenone series (2) of nonsteroidal selective androgen receptor modulators (SARM) was developed based on the 6-aryl-2-quinolinones (1). Synthesis and preliminary SAR results based on in vitro assays are discussed. In the cotransfection assay,

Full text of DOI:10.1016/j.bmcl.2008.03.085

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Bioorganic & Medicinal Chemistry Letters 18 (2008) 3431–3435
Discovery of a novel series of nonsteroidal androgen
receptor modulators: 5- or 6-oxachrysen-2-ones
Shuo Zhao,* Yixing Shen, Arjan van Oeveren, Keith B. Marschke and Lin Zhi*
Discovery Research, Ligand Pharmaceuticals Inc., 10275 Science Center Drive, San Diego, CA 92121, USA
Received 4 February 2008; revised 24 March 2008; accepted 31 March 2008
Available online 8 April 2008
Abstract—A novel oxachrysenone series (2) of nonsteroidal selective androgen receptor modulators (SARM) was developed based
on the 6-aryl-2-quinolinones (1). Synthesis and preliminary SAR results based on in vitro assays are discussed. In the cotransfection
assay, lead compound 5d showed AR agonist activity more potent than dihydrotestosterone (DHT), whereas compound 17b was a
potent antagonist similar to bicalutamide.
Ó 2008 Elsevier Ltd. All rights reserved.
6
Y
Testosterone replacement therapy may be beneficial to
the quality of life of men in middle age and beyond, akin
to the role of estrogen replacement for symptomatic
peri- and postmenopausal women.1 Although the bene-
ficial effects of testosterone on muscle, bone, and phy-
sique have been reported, considerable controversy
remains for testosterone supplementation in aging
men, especially the issue of potential risks (cardiovascu-
lar disease, benign prostatic hyperplasia, prostate can-
cer, hepatotoxicity, etc.).2 The discovery and
development of Selective Androgen Receptor Modula-
tors (SARMs) provide the opportunity to find nonste-
roidal, orally active small molecules that are tissue-
selective and elicit the desired anabolic activity with re-
duced side effects.3,4
R1
5
R1
X
D
C
R2
R2
R3
A
N
H
B
R3
O
N
H
O
1
2
Figure 1.
aminobromobenzocoumarin 312 with but-3-enoyl chlo-
ride provides amide 4. Intramolecular palladium cata-
lyzed cyclization provides 6-oxa-chrysen-2-ones 5.
Reduction of compound 5 with diisobutylaluminum
hydride provides hemiacetal 6, which can be further
reduced with triethylsilane and boron trifluoride ether-
ate to provide analogs of structure 7. Alternatively,
hemiacetal 6 is converted to acetal 8, by treatment
with acid (such as p-TSA) in methanol. Racemate
mixture of analogues 9 can be prepared by treating
acetal 8 with a nucleophile in the presence of boron
trifluoride etherate.
Several different nonsteroidal SARM pharmacophores
have been reported,5 such as aryl-propionamides,6 bicy-
clic hydantoins,7 tetrahydro-quinolines,8 and indole-
containing tetracycles.9 As part of our efforts10 to devel-
op novel SARMs with more desirable pharmacological
profiles, here we report a novel series of tetracyclic
androgen receptor modulators (structure 2, Figure 1)
that was designed based on an early 6-aryl-2-quinoli-
none SARM lead (1) by locking the rotation of the pen-
dent aryl group.11
Regioisomeric 5-oxa-chrysen-2-ones 15 and 17 were syn-
thesized as described in Scheme 2. Selective methylation
of known intermediate 1013 with methyl iodide and so-
dium bicarbonate affords compound 11, which under-
goes selective O-alkylation to afford compound 12.
Suzuki coupling of 12 and boronic acids14 13 affords
intermediates of structure 14. Cyclization of structure
14 in concd HBr and AcOH affords lactone 15. Reduc-
tion of lactone 15 by diisobutylaluminum hydride af-
fords acetal 16 that was converted to analogues 17 by
A general route for the synthesis of 6-oxa-chrysen-2-
ones is shown in Scheme 1. Treatment of a known
Keywords: Androgen receptor; SARM; AR agonist; AR antagonist;
Oxachrysen-2-ones.
*
Corresponding authors. E-mail: szhao2005@gmail.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.085

3432
S. Zhao et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3431–3435
O
O
O
O
O
O
Br
R2
a
b
Br
R2
O
R2
R3
R3
N
R3
O
N
H
H2N
H
4
5
3
O
HO
O
c
d
R2
R2
R3
O
N
H
R3
O
N
H
6
7
e
R4
O
O
O
f
R2
R2
R3
R3
O
N
O
N
H
H
8
9
Scheme 1. Reagents and conditions: (a) CH2@CHCH2COCl, DMAP, DMF, reflux, 50–70%; (b) Pd(OAc)2, (o-tolyl)3P, Et3N, DMF, 90 °C, 30–60%;
(c) DIBAL-H, CH2Cl2, 0 °C, 40–85%; (d) Et3SiH, BF3ÆOEt2, CH2Cl2, À78 to 0 °C, 40–80%; (e) p-TSA, MeOH, rt, >95%; (f) trimethylsilanes,
BF3ÆOEt2, CH2Cl2, À78 to 0 °C, 50–90%.
CF3
N
O
CF3 OH
CF3
O
Br
b
a
Br
Br
O
O
N
H
O
N
H
12
10
11
CONEt2
Et2NOC
(HO)2B
R3
13
CF3
O
d
R2
R3
R2
O
N
c
14
O
OH
CF3
O
CF3
O
CF3
O
f
R2
R2
e
R2
R3
R3
R3
O
N
H
O
N
O
N
H
H
17
16
15
Scheme 2. Reagents and conditions: (a) CH3I, NaHCO3, DMF, rt, 85%; (b) 2-iodopropane, CsF, DMF, rt, 89%; (c) Pd(PPh3)4, 2 M Na2CO3, 1,4-
dioxane, 110 °C, 40–60%; (d) 48% HBr/HOAc, reflux, 50–70%; (e) DIBAL-H, CH2Cl2, 0 °C, 70–85%; (f) Et3SiH, BF3ÆOEt2, CH2Cl2, À78 to 0 °C,
30–65%.
treatment of acetal 16 with triethylsilane in the presence
of boron trifluoride etherate.
data as references. The IL-6 promoter assay in bone
cells16 was used as secondary assay to indicate potential
anabolic bone activity for agonists and potential bone-
sparing antagonists. The human androgen receptor
(hAR) competitive binding affinities of the analogs, their
We used the cotransfection assay9,15 data to guide SAR
studies and to characterize analogs, and binding assay9

Table 1. hAR agonist and antagonist activity in the cotransfection assay in CV-1 cells, binding affinities to hAR, and repression activity in IL-6 assaya
O
R4
O
O
O
O
CF3 O
CF3 O
CF3
R2
R2
R2
R2
R2
R3
R3
R3
R3
R3
O
N
H
O
N
O
N
H
O
N
H
O
N
H
H
15
5
9
18
17
Compound
R2
R3
R4
hARb EC50 in nM (Eff.)
hARc IC50 in nM (Eff.)
hAR binding Ki (nM)
Saos-2 IL-6 repressiond IC50 in nM (Eff.)
5a
5b
F
OCH3
H
H
240 99 (22 5%)
—
27 2 (57 11%)
48 14 (62 17%)
1000
610
101 0 (50 1%)
0.8 0.0 (55 10%)
21 28 (97 18%)
1.9 0.2 (104 4%)
0.2 0.0 (110 3%)
0.2 0.1 (112 4%)
10 9.4 (84 2%)
2.8 1.2 (76 1%)
12 9 (70 5%)
0.3 (99%)
5c
5d
H
OCH3
11 8 (72 19%)
1.1 0.1 (132 8%)
21 6 (117 11%)
43 14 (97 13%)
18 0.7 (33 13%)
23 8 (21 6%)
50 14 (70 13%)
12 2.0 (156 22%)
306 102 (118 0.2%)
208 78 (93 8%)
184 23 (27 1%)
—
—
—
28 1.0
8.7
4.0 1.5
H
OH
O2CC(CH3)3
OCH3
OCH3
OCH3
OCH3
OCH3
CH2OH
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OH
5e
—
—
5f
5g
O2CC(CH3)3
OCH2CH3
OCH(CH3)2
10
62
4
—
20 3 (29 9%)
5h
9a
21
59
H
H
OH
H
H
H
H
H
H
H
H
H
H
H
—
—
9b
9c
H
26
5
H
OH
19 0 (47 24%)
—
1.2 0.5 (96 18%)
50 0 (72 17%)
112 0 (54 5%)
No data
9d
9e
1300
2346
250
1593
11
OCH3
CH3
Allyl
19 0 (49 3%)
62 30 (63 10)
9f
9g
—
144 77 (63 6%)
—
No data
18a
18b
20 3 (67 10%)
16 12 (138 6%)
90 0 (33 9%)
97 52 (65 55%)
60 2 (34 8%)
—
5
14 3 (97 3%)
1.1 0.2 (97 6%)
89 17 (76 3%)
22 3 (93 6%)
40 (91%)
—
—
1.3
50
15a
15b
OCH3
OH
—
—
3
17a
17b
H
OCH3
8
27
4
78 57 (68 9%)
—
162 99 (85 9%)
477 0 (42 12%)
0.05 (100%)
232 84 (28 8%)
DHT
Bicalutamide
5.1 0.1 (100%)
—
0.20 0.02
151 36
a Values with standard errors represent the mean value of at least 2 separate experiments with triplicate determinations. A dash indicates an efficacy of <20% and/or a potency of >10,000 nM.
b Agonist efficacies were determined relative to DHT (100%).
c Antagonist efficacies (%) were determined as a function of maximal inhibition of DHT at the EC50 concentration.
d Due to the repression format of the assay, IC50 may not be accurate for activity comparison if efficacy is below 60%.

3434
S. Zhao et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3431–3435
hAR functional activity in CV-1 cells, and IL-6 repres-
sion assay results are summarized in Table 1. DHT
and bicalutamide were used as references.
despite potential enhancement by the 4-trifluoromethyl
group. The 10-hydroxyl analog 15b also demonstrated
significant improvement to the 10-methoxy compound
15a in all three assays tested. Finally, the 5-oxa analog
17a had interesting partial agonist activity, although it
has no substitution at the 10-position. Compound 17b
had decent antagonist activity in comparison with bica-
lutamide in the assays, which is quite distinct from the 6-
oxa analog 18a.
SAR studies of the series were initiated from the lactone
compounds of structure 5. Early compounds 5a and b
showed interesting partial antagonistic activities regard-
less of their distinct property of substitution groups at
the 9-position and weak AR binding as seen in many
antagonists. These results are consistent with the parent
analogs of structure 1. When the methoxy group at 9-
position (5b) was moved to 10-position (5c), the func-
tional activity in the hAR cotransfection assay totally
shifted from a partial antagonist to agonist. In the IL-
6 assay, the substitution position change increased effi-
cacy of compound 5c to 97% of DHT from 55% for
compound 5b. Compound 5d with an ester functionality
at 10-position represented an example of a potent hAR
full agonist with good binding affinity. The bis-substitu-
tion at 9- and 10-positions was briefly studied and com-
pound 5e with 9-hydroxyl-10-methoxy gave the best full
agonist activity (1.1 nM EC50 and 132% efficacy). Com-
pound 5f with a bulky ester group at 9-position also
showed excellent agonist activity similar to that of 5e,
which may be the result of partial hydrolysis of the ester
in the assays since compounds 5g and h, which have sim-
ilar bulky 9-substituents, had only partial activity.
Cross-reactivity of the new compounds with other ste-
roid hormone receptors was assessed using human PR
(hPR) and glucocorticoid receptor (hGR) cotransfection
assays. The results (not shown) indicate that the com-
pounds are highly selective towards hAR. Only com-
pound 5d showed appreciable hPR antagonist activity
(IC50 = 269 nM and 67% efficacy).
In summary, the oxachrysenone hAR modulator phar-
macophore was successfully established, which provides
additional SAR opportunities to develop more selective
SARMs to meet the unmet patient needs. Several full
agonist compounds (5d, 5e, 9b, and 18b) were generated
with potential anabolic bone activity and a couple of
partial antagonists (9c and 17b) were also generated with
potential advantage over bicalutamide. The pharmaco-
kinetic property and the in vivo tissue selectivity profiles
of the compounds remain to be characterized.
To assess necessity of the lactone moiety, the carbonyl
group of two compounds at 5-position was fully reduced
to give cyclic ether compounds 9a and c. Removal of the
carbonyl group reduced the hAR EC50 of 5c (11 nM) by
5-fold (9a, EC50 = 50 nM) and of 5e (21 nM) by 30-fold
(9c, EC50 = 306 nM), although the binding affinity of 9c
and 5e is similar. Interestingly, replacement of the 10-
methoxy group of 9a with 10-methylalcohol (9b) gener-
ated a potent full agonist. The lactone analog of 9b is
not prepared due to synthetic challenges so that general-
ity of the substitution enhancement is difficult to say.
Another intriguing profile is the mixed agonist/antago-
nist compound 9c, which had both moderate agonist
activity (EC50 = 306 nM with 118% efficacy) and potent
partial antagonist activity (IC50 = 19 nM with 49% effi-
cacy) in the cotransfection assay. Additionally, it had
excellent hAR binding affinity and DHT-like activity
in the bone cell assay.
Acknowledgment
We thank the Department of New Leads for performing
the assays.
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