Discovery of 6-N,N-Bis(2,2,2-trifluoroethyl)amino-4- trifluoromethylquinolin-2(1H)-one as a novel selective androgen receptor modulator

Article abstract of DOI:10.1021/jm060792t

The androgen receptor is a member of the extended family of nuclear receptors and is widely distributed throughout the body. Androgen therapy is used to compensate for low levels of the natural hormones testosterone (T) and dihydrotestosterone and consist

Full text of DOI:10.1021/jm060792t

J. Med. Chem. 2006, 49, 6143-6146
6143
Scheme 1a
Discovery of 6-N,N-Bis(2,2,2-trifluoroethyl)amino-
4-trifluoromethylquinolin-2(1H)-one as a Novel
Selective Androgen Receptor Modulator#
Arjan van Oeveren,* Mehrnouch Motamedi,
Neelakandha S. Mani,† Keith B. Marschke,
Francisco J. Lo´pez, William T. Schrader,‡
Andre´s Negro-Vilar, and Lin Zhi
DiscoVery Research, Ligand Pharmaceuticals Inc.,
10275 Science Center DriVe, San Diego, California 92121
ReceiVed July 6, 2006
Abstract: The androgen receptor is a member of the extended family
of nuclear receptors and is widely distributed throughout the body.
Androgen therapy is used to compensate for low levels of the natural
hormones testosterone (T) and dihydrotestosterone and consists of
administration of T, prodrugs thereof, or synthetic androgens. However,
currently available androgens have many drawbacks. We identified
6-dialkylamino-4-trifluoromethylquinolin-2(1H)-ones as orally available
tissue-selective androgen receptor modulators.
a Reagents: (a) HNO3, H2SO4, -5 to 4 °C, 20 min; (b) Pd/C 10%, H2,
dimethylformamide, 6 h; (c) NaCNBH3, MeOH, aldehyde or ketone, with
or without acetic acid; (d) trifluoroacetic acid, NaBH4, room temp to 50
°C, 2 days.
tural classes have been developed and marketed.10 AR is widely
distributed in tissues such as the prostate, seminal vesicle, male
and female genitalia, skin, testis, ovary, cartilage, sebaceous
glands, hair follicles, sweat glands, cardiac muscle, smooth
muscle, gastrointestinal vesicular cells, thyroid follicular cells,
adrenal cortex, liver, pineal, and brain.11 Tissue selectivity is
dependent on the regulation of AR expression, differential DNA
binding at the promotor of regulated genes, and tissue-specific
protein-protein interactions.12 In addition, cross-talk with other
tissue-specific signaling components, nongenomic effects, and
heterodimerization with other receptors may contribute to tissue
selectivity.13 Some steroidal androgens such as 7R-methyl-
nortestosterone (MENT)14 have shown tissue selectivity in
clinical trials, with greater efficacy in anabolic endpoints, such
as bone, than in androgenic endpoints, such as the prostate gland.
However, such effects on the skeleton may be due to its
conversion to estrogens, while the reduced effects in the
androgenic endpoints are thought to be due to limited 5R-
reduction.
The natural hormones testosterone (Ta) and dihydrotestoster-
one (DHT) play important roles in male sexual development
and function and in musculoskeletal growth. Deficiencies of
circulating levels of these hormones in hypogonadal men can
be treated by administration of exogenous androgens.1,2 An-
drogen therapy has been available to physicians for many years
now. However, unlike female sex hormone therapies, which
have found extensive use in the fields of hormone replacement
therapy, reproductive disorders, and contraception, androgen
therapy has not been widely used. The reasons for this limited
use are twofold. First, the beneficial effects of steroidal androgen
therapies are overshadowed by potential side effects, some of
which are due to their rapid metabolism to DHT and estrogens.
Second, most steroidal androgens undergo rapid first pass
hepatic metabolism and therefore cannot be taken orally.
Commonly used methods of administration of T have been
intramuscular injections or transdermal patches.3 Alkylation of
steroidal androgens at C17 slows hepatic metabolism, thus
rendering them suitable for oral administration, but these
compounds can lead to potential liver toxicity and are therefore
not appropriate for chronic use.4 Besides the search for safer,
orally available androgens, much focus has been devoted to the
development of androgens that separate the desired anabolic
effects from the undesired androgenic effects.5 Selectivity has
been demonstrated for modulators of different steroid hormone
receptors, such as the estrogen (ER),6 progesterone (PR),7 and
glucocorticoid (GR)8 receptors. More recently, tissue-selective
AR modulators have been reported, some of which are based
on nonsteroidal androgen antagonists,9 of which several struc-
We identified a novel AR modulator 4m (LGD2226) from
SAR studies of a series of 6-N,N-dialkylamino-4-trifluoro-
methylquinolin-2(1H)-ones. In addition to the benefits of being
orally available, this compound demonstrated tissue selectivity
in animal models, with reduced effects on prostate compared
to muscle.15
The synthesis of 6-N,N-dialkylamino-4-trifluoromethylquino-
lin-2(1H)-ones is outlined in Scheme 1. Compound 1 was pre-
pared following a slight modification of the procedure reported
by Berbasov and Soloshonok.16 Nitration of 1 (H2SO4, HNO3,
-5 to 4 °C) afforded a mixture of 6- and 8-nitroquinolinones
in a ratio of approximately 9:1 in favor of the desired
6-nitroquinolinone. A single crystallization from ethanol/water
afforded pure 2. The nitro group was reduced with Pd/C under
a hydrogen atmosphere to give aniline 3. Alkyl substituents on
the amine were introduced by reductive alkylation, using
NaCNBH3 and the appropriate aldehyde or ketone. Depending
on the reaction conditions and reagents used, either mono- or
bisalkylation could be achieved. Ketones gave only monosub-
stituted amines, while aldehydes gave bisalkylation when acetic
acid was added to the reaction mixture. In the absence of acid,
monoalkylation was observed with most aldehydes. Only
formaldehyde and acetaldehyde gave significant amounts of
# Presented in part at the 29th National Medicinal Chemistry Symposium,
Madison, WI, June 27 through July 1, 2004.
* To whom correspondence should be addressed. Phone: 1-858-550-
7870. Fax: 1-858-550-7249. E-mail: avanoeveren@ligand.com.
† Present address: Johnson & Johnson PRD, 3210 Merryfield Row, San
Diego, California, 92121.
‡ Present address: Laboratory of Reproductive and Developmental
Toxicology, National Institute of Environmental Health Sciences, Research
Triangle Park, NC.
a Abbreviations: AR, Androgen receptor; SARM, selective androgen
receptor modulator; T, testosterone; DHT, dihydrotestosterone; ER, estrogen
receptor, PR, progesterone receptor; GR, glucocorticoid receptor; MR,
mineralocorticoid receptor; ORDX, orchidectomized.
10.1021/jm060792t CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/22/2006

6144 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 21
Letters
Table 1. Cotransfection and Competitive Binding Data for 6-(N,N-Dialkylamino)-4-trifluoromethylquinolin-2(1H)-ones and DHTa
hAR agonist
EC50 (nM)
hAR agonistb
Eff (%)
hAR antagonist
IC50 (nM)
hAR antagonistc
Eff (%)
hAR whole-cell
binding Ki (nM)
compd
R1
R2
3
H
H
H
CH3
H
-
-
26
28 ( 7
72 ( 3
61 ( 4
72 ( 4
-
>10 × 103
4a
4b
4c
4d
4e
CH2CH2CH3
CH(CH3)2
CH3
2022
34
27.5 ( 5.5
54
106
-
2.1 ( 0.3
1.5 ( 0.2
1283
2.2 ( 0.4
1.9 ( 0.7
0.4 ( 0.1
2.8 ( 1.6
0.2 ( 0.02
5.1 ( 0.1
26
-
94 ( 19
72 ( 5
68
77 ( 13
81 ( 8
107 ( 5
99 ( 13
95 ( 2.0
100 ( 0.08
16.5 ( 0.5
58
153
4.4
64
222
7.4
6.3
7.1
7.1
1.5
34 ( 11
CH2CH3
CH2CH3
-
-
CH2CH2CH3
CH2CH2CH2CH3
CH2CH3
CH2(c-C3H5)
CH2CH3
CH2CH2CH3
CH2CH2CH2CH3
CH(CH3)2
CH2(c-C3H5)
CH2CF3
-
4f
29.5 ( 6.5
54 ( 1
-
4g
4h
4k
4l
4m
DHT
-
-
-
-
-
-
-
-
CH2(c-C3H5)
CH2CF3
CH2CF3
CH2CF3
-
-
-
0.2 ( 0.02
a Values with standard errors represent the mean value of at least two separate experiments with triplicate determinations. A dash indicates an efficacy
of <20% and a potency of >10000 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 value.
bisalkylated product. Sometimes it proved to be more convenient
to introduce the alkyl substituents by the reaction of carboxylic
acids with NaBH4 in the presence of the amine.17 This procedure
was especially useful for introduction of a trifluoroethyl
substituent. The bis-trifluoroethyl-substituted amine 4m was
obtained in 83% yield from the reaction of 3 with trifluoroacetic
acid and NaBH4.
To determine the binding mode of 4m in the androgen
receptor, a cocrystal structure was obtained with 4m in the hAR
ligand binding domain (Figure 1b). As expected, 4m occupies
the same binding pocket as DHT (Figure 1a),19 and in general,
the protein backbone is superposable to that observed with DHT.
Just like the carbonyl group of DHT, the quinolone carbonyl
forms hydrogen bond interactions with GLN711 and ARG752.
GLN711 forms an additional hydrogen bond with the quinolone
NH of 4m. The trifluoroethyl groups of 4m occupy the same
space in the receptor as the C and D rings of the steroid. The
dimethyl-substituted analogue 4c would not be able to fully
occupy this space in the binding pocket, and this explains the
reduced binding affinity and antagonist activity observed for
this compound. On the other hand, the dipropyl analogue 4e
would still fit very well, but the dibutyl compound 4f is too
big, resulting in strongly reduced binding affinity and antagonist
activity in the cotransfection assay. A further in depth discussion
of the cocrystal structure of 4m in the hAR ligand binding
domain will be published separately.20
The in vivo activity of 4m was evaluated in mature orchi-
dectomized (ORDX) rats. After ORDX the rats were orally
dosed for 2 weeks with 4m in a dose range from 1 to 100 mg/
kg or vehicle. Sham operated rats were used as control. The
same experiment was run with testosterone as a positive control.
Because of the rapid metabolism of testosterone in the liver,
testosterone was dosed subcutaneously. After 2 weeks of dosing,
the weight of the ventral prostate was determined as a measure
of androgenic activity. The weight of the levator ani muscle
was determined as a measure of anabolic activity. The results
of the 2-week ORDX rat in vivo experiment are shown in Figure
2. 4m has a pronounced effect on the levator ani muscle,
maintaining the muscle weight at the eugonadal levels at an
approximate 3 mg/kg dose. At higher doses, levator ani muscle
weight increases up to 150% of intact rats. This demonstrates
that 4m is a highly potent anabolic androgen. In marked contrast,
4m had weak trophic effects on the prostate. An amount of 100
mg/kg 4m was required to maintain prostate weight at intact
levels. These data clearly show the tissue selectivity of 4m. In
contrast, testosterone maintained the levator ani muscle weight
and the ventral prostate weight at the eugonadal level at the
same dose of approximately 2 mg/kg. From Figure 2 it is also
The in vitro activity of 6-N,N-dialkylamino-4-trifluoromethyl-
quinolin-2(1H)-ones (4a-m) on the human AR was studied in
a cellular background using a cotransfection assay.18 Ligand-
dependent stimulation of a luciferase reporter gene was mea-
sured against the concentration of ligand. The compounds were
also tested in the antagonist mode in the presence of DHT at
its EC50. The binding affinity for the hAR was measured in a
whole-cell receptor binding assay. The results for the differen-
tially substituted 6-aminoquinolin-2(1H)-ones in the cotrans-
fection and binding assays are listed in Table 1. The substituents
had a large effect on the activity of the compounds in the cell-
based assay. The unsubstituted or monosubstituted amines (3,
4a, 4b) were mainly antagonists with a hint of agonist activity
for 4a and 4b. Also, the dimethylamine 4c turned out to be an
antagonist in this assay. The optimal length for the alkyl
substituents was two or three carbons, as exemplified by the
excellent potency and efficacy of the diethyl 4d and dipropyl-
amine 4e. The dibutylamine 4f, however, was a weak partial
agonist with some antagonistic activity. Having one alkyl group
branched as in the ethylisopropyl analogue 4g resulted in a good
agonist. The bis-cyclopropylmethylamine 4h was a very potent
and efficacious compound, but the best agonists had a trifluoro-
ethyl substituent on the amine. Both 4k and 4m had subnano-
molar potencies in the cotransfection assay. The bis-trifluoro-
ethylamine 4m was more potent (EC50 ) 0.2 ( 0.02 nM) than
DHT (EC50 ) 5.1 ( 0.1 nM) and showed efficacy comparable
to that of the steroid. No antagonist activity was observed in
this assay. In the competitive whole-cell binding assay, 4m had
a Ki of 1.5 nM, compared to 0.2 nM for DHT. Compound 4m
was specific for AR, showing no significant binding affinities
for PR, GR, MR, and ER (Ki > 1 µM, data not shown).
Similarly, agonist or antagonist mode cross-reactivity was not
observed in cotransfection assays with these nuclear receptors
for concentrations of 4m up to 10 µM (data not shown).

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 21 6145
the cocrystals involve only the ligand-binding domain, tissue
selectivity may also reside in structural domains of the AR that
were not included in the current analysis.
In conclusion, we have identified 4m as an AR-specific
nonsteroidal androgen, which exhibited efficacy and potency
in maintaining levator ani muscle weight similar to testosterone.
Furthermore, the compound exhibited much less efficacy and
potency compared to T in stimulating the ventral prostate weight
of mature castrated rats. Since 4m demonstrates a clear
separation between androgenic (ventral prostate) and anabolic
(levator ani muscle) endpoints in an in vivo model, it can
therefore be classified as a selective androgen receptor modulator
(SARM).
Acknowledgment. We thank the Department of New Leads
for performing in vitro and competitive binding assays, the
Department of Pharmacology for performing the in vivo assays,
Professor Tao Jiang, the Institute of Biophysics, Chinese
Academy, for obtaining the cocrystal structure, and Dr. Adam
Kallel for generating the pictures in Figure 1.
Supporting Information Available: Synthetic procedures,
chemical characterization data for 1-4, and biological assay
methods. This material is available free of charge via the Internet
at http://pubs.acs.org.
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