Discovery and development of antiandrogens

The first antiandrogen was discovered in the 1960s. Antiandrogens antagonise the androgen receptor (AR)
and thereby block the biological effects of testosterone and dihydrotestosterone (DHT). Antiandrogens are
important for men with hormonally responsive diseases like prostate cancer, benign prostatic hyperplasia
(BHP), acne, seborrhea, hirsutism and androgen alopecia. Antiandrogens are mainly used for the treatment
of prostate diseases.[1][2][3] Research from 2010 suggests that ARs could be linked to the disease
progression of triple-negative breast cancer and salivary duct carcinoma[4] and that antiandrogens can
potentially be used to treat it.[5][6]

As of 2010 antiandrogens are small molecules and can be either steroidal or nonsteroidal depending on
ligand chemistry. Steroidal antiandrogens share a similar steroid structure, while nonsteroidal antiandrogens
(NSAAs) may have structurally distinctive pharmacophores. Only a limited number of compounds are
available for clinical use despite the fact that a very large variety of antiandrogen compounds have been
discovered and researched.[2]

History
At the beginning of the twentieth century, a relationship between the pituitary, testes and prostate gland had
been established. American physician Charles Brenton Huggins found out that castration or estrogen
administration led to glandular atrophy in men, which could be reversed by re-administration of androgen.
In 1941 Huggins treated prostate cancer patients by androgen ablation with either castration or estrogen
therapy; the beneficial effect of androgen ablation on metastatic prostate cancer was realised, for which he
was awarded the Nobel Prize in Physiology or Medicine in 1966.[1]

It became evident that androgen ablation alone was insuffient to cure patients with advanced prostate
cancer. In the late 1960s, the androgen receptor (AR) was discovered and characterized. Screening of
chemical libraries for AR blockers led to the discovery of the first antiandrogen, cyproterone. An acetate
group was then added to cyproterone and created cyproterone acetate. In the 1970s, the antiandrogen
flutamide was discovered. In 1989 the United States Food and Drug Administration (FDA) approved it for
use the treatment of prostate cancer. In 1995, bicalutamide was approved, and nilutamide followed a year
later.[1][7]

Androgen receptor
The AR belongs to the steroid receptor subfamily of the nuclear receptor superfamily. Its function is
regulated by the binding of androgens, which initiates sequential conformation changes of the receptor that
affects receptor-protein and receptor-DNA interactions. Endogenous androgens are mainly testosterone and
DHT.[8][9][10][11] AR is expressed in cells of a wide range of tissues, throughout the entire body, beyond
primary and secondary sexual organs.[12]

The AR gene is more than 90kb long and codes for a protein of 919 amino acids. Only one AR gene has
been identified in humans which is located on chromosome X. It comprises four main regions, see figure
1:[2][3][7][8]

1. N-terminal domain (NTD) which serves a modulatory function.

 2. DNA-binding domain (DBD) which
recognises and binds to androgen
response elements (ARE) in target
gene sequence.
3. Ligand binding domain (LBD)
which is responsible for ligand
recognition and binding.
4. A small hinge region between the
DBD and LBD.

Two functions have been identified in AR

that have critical roles in the regulation of
target gene transactivation, the N-terminal
activation function 1 (AF1) and the C- Figure 1 The four main regions of the androgen receptor
terminal activation function 2 (AF2). AF1
is ligand-independent and plays the primary
role in target gene transactivation. The AF2 is a ligand-dependent and only shows limited function.[8][10]

Mechanism of action

Unbound AR is mainly located in the cytoplasm, like a typical steroid receptor, and is associated with a
complex of heat shock proteins (HSP) through interactions with LBD. Androgens, either agonists or
antagonists, position themselves in the ligand-binding pocket (LBP) of the cytosolic AR and bind to the
LBD, see figure 2. The AR goes through a series of conformational changes and HSP dissociate from AR.
The transformed AR undergoes dimerisation, phosphorylation and translocates to the nucleus. The
translocated receptor then binds to the androgen-response elements (ARE) on the promoter of the androgen
responsive gene, a consensus sequence located either upstream or downstream of the transcription start site
(TSS) of AR target genes. Recruitment of other transcription co-factors (including co-activators and co-
repressors) and general transcriptional machinery further ensures the transactivation of AR-regulated gene
expression. All these complicated processes are initiated by the ligand-induced conformational changes in
the LBD. Ligand specific recruitment of coregulators might be crucial for the agonist or antagonist activity
of AR ligands. Binding of DNA is also required for AR-regulated gene expression, also known as classic
genomic gene function of AR.[7][8][10]

Development of antiandrogens
Cyproterone is a steroidal antiandrogen that competitively inhibits the binding of testosterone or DHT to
AR. Cyproterone binds to ARs that are expressed by prostate cancer cells as well as to the AR that are
expressed in the hypothalamus and pituitary. Therefore, cyproterone blocks the negative feedback of
androgens at the hypothalamic-pituitary level leading to increased luteinizing hormone (LH) serum levels.
This rise in LH levels causes an increase in serum testosterone levels and ultimately diminishes the ability
of cyproterone to compete for AR binding and to block androgenic stimulation.[1][7]

Cyproterone acetate was developed to overcome this problem. It is formed by adding an acetate group to
cyproterone, see figure 3. Cyproterone acetate has a dual mode of action as it competes directly with DHT
for binding to AR, but also inhibits gonadotropin secretion. It thereby reduces androgen, estrogen and LH
levels.[1][7] Cyproterone acetate acts both directly as an antiandrogen in prostate cancer cells and also
functions to indirectly decrease serum testosterone levels. The latter causes the limitations of cyproterone
acetate, which are central effects on androgen secretion, with subsequent loss of libido and sexual potency.
Several reports also state that cyproterone acetate causes liver hyperplasia. These side effects gave
pharmaceutical companies the incentive to search for alternative, "pure" NSAAs that would not have these
side effects.[1] Pure antiandrogens block the androgen receptor without exerting any agonistic or any other
hormonal activity.[3]

Flutamide became the first NSAA to be tested clinically. Later the NSAAs bicalutamide and nilutamide
were developed. The alleged advantages of these compounds were that they did not affect libido or potency
like the other centrally acting compounds under development, luteinizing-hormone-releasing hormone
(LHRH) agonists and cyproterone acetate. But this theory did not prove to be true. These NSAAs
eventually crossed the blood–brain barrier, like cyproterone acetate, leading to a subsequent increase in
serum testosterone levels.[1]

Flutamide

Flutamide is an arylpropionamide analog with pure antiandrogenic

properties, seen in figure 4. It is completely absorbed from the
gastrointestinal tract after oral administration and undergoes
extensive first pass metabolism to its active form, 2-
hydroxyflutamide, and hydrolysis product, 3-trifluoromethyl-4-
nitroaniline.[7][9][10] Hydroxyflutamide is a more potent AR
antagonist than flutamide in vivo, with higher binding affinity for
Figure 4 Flutamide
the AR. Hydroxyflutamide has an elimination half-life of about 8
hours in humans. Hydrolysis of the amide bond represents the
major metabolic pathway for this active metabolite. By reversing
the stimulatory effect of DHT on ventral prostate weight, flutamide is approximately 2-fold more potent
than cyproterone acetate. Hydroxyflutamide has relatively low binding affinity to AR and is therefore
generally used at high doses in order to achieve complete AR blockage in therapy.[9][13]

Nilutamide

Nilutamide is a nitroaromatic hydantoin analog of flutamide, as

seen in figure 5.[9][10] Nilutamide is eliminated exclusively by
metabolism, mainly by reduction of the aromatic nitro group.
Although the hydrolysis of one of the carbonyl functions of the
imidazolinedione was identified, it is much less susceptible to
hepatic metabolism than the amide bond in hydroxuflutamide. This
results in a longer half-life of nilutamide in humans of 2 days.
Nevertheless, the nitro anion-free radical formed during nitro
reduction could still be associated with hepatotoxicity in humans, Figure 5 Nilutamide
especially when using relatively high dosage employed for
androgen blockage.[9] Nilutamide causes side-effects which limit its
usage, such as pneumonitis and delayed adaption to darkness.[7]

Bicalutamide

Bicalutamide is an arylpropionamide analog, seen in figure 6.[9][10] It has replaced flutamide and
nilutamide as the first choice antiandrogen for prostate cancer treatment. Bicalutamide is not as hepatotoxic
as flutamide and nilutamide and has a longer half-life, of 6 days in humans, that allows once a day
administration at lower dosage. Bicalutamide shares
the amide bond structure with flutamide. Even so, the
amide bond hydrolysis was discovered in rats, not in
humans, which could explain the prolonged half life of
bicalutamide in humans.[9]

Bicalutamide has a cyano group at the para position Figure 6 Bicalutamide

instead of a nitro group like flutamide and nilutamide.
This change in groups avoids the nitro reduction
observed in nilutamide. Bicalutamide has a chiral carbon in its structure (labeled with an asterisk in figure
6), which is connected to the hydroxyl and methyl groups . It is therefore administered as a racemate.[9]
Post-approval investigation revealed that its antiandrogenic activity resides almost entirely in the (R)-
enantiomer. (R)-bicalutamide has an almost fourfold higher affinity for the prostate AR than
hydroxyflutamide and has a better side-effect profile compared to other antiandrogens.[9][10]

Structure and activity relationship

Steroidal antiandrogens

Cyproterone acetate is a 6-chloro-1,2-methylene derivative of 17α-acetoxyprogesterone. It shows major

antiandrogenic activity together with androgenic activities. Cyproterone acetate displays high affinity for
AR in rats which increases when the 1,2-methylene group is removed from the compound. If the chlorine
atom is replaced by a methyl group the binding slightly decreases, whereas further removal of the C6
double bond modifies the binding kinetics, see figure 7.[3]

Hydroxyflutamide Bicalutamide
Nilutamide
Figure 7: Basic structures of current antiandrogens

Nonsteroidal antiandrogens

Hydroxyflutamide and its analogues, bicalutamide and nilutamide, share an anilide ring structure. The
structures can be seen in figure 7, where the anilide ring is coloured red. These three compounds require an
electron-deficient aromatic ring for efficient AR binding. Replacing the anilide with an alkene gives weakly
active compounds, which can be attributed to the lack of intramolecular hydrogen binding or to poor
hydrogen-bond donor capability.[3] Various combinations of electron-withdrawing substitutions in the
aniline ring of these drugs have not shown higher binding to the AR receptor, compared to compounds
which have a chloro or trifluoromethyl group at the meta position (R1) and either a cyano or nitrogen group
at the para position (R2).[3][14]

For hydroxyflutamide, a group of compounds that differed in the aromatic ring did not bind to the AR. This
suggests that the bisubstitution in the hydroxyflutamide ring is essential for high AR binding affinity. It has
also been demonstrated that hydroxyflutamide requires the strong hydrogen bond donor ability of the
tertiary hydroxyl group and fixed conformers involved in intramolecular hydrogen binding, to bind
effectively to AR.[3][14]

For bicalutamide, the antiandrogenic activities of sulfide and sulfone substitutions of the X-linkage were
tested in vitro. The sulfides showed in most cases at least 2-fold higher binding affinity than corresponding
sulfones. However, this relationship was reversed when the R3 group was NHSO2 CH3 , where the binding
affinity of sulfone was 3-fold higher than that of sulfide. These results indicate that substituents of the B-
ring largely determine the effect of the X-linkage in AR binding. Researchers have proposed that the
tertiary hydroxyl group is involved in direct interaction with AR because when an acetyl group is
introduced to that hydroxyl moiety, the receptor binding affinity greatly decreases.[14]

Nilutamide has very low affinity for AR when tested on castrated rat prostate. Modifications such as
replacing the N3 atom with oxygen has little effect on affinity of the compound for prostate AR. By
replacing the oxygen atom with a sulfur atom at the C2 position of the imidazole ring and adding
butylalcohol to the N3 atom, the receptor binding and biological activity of the compound increases 100
times that of NSAAs. Also the compound does not bind to other steroid receptors. If a methyl group is
changed for the butylalcohol group, the compound shows 3 and 10 times more antiandrogenic activity in
vivo than bicalutamide and nilutamide, respectively.[3]

Antiandrogen withdrawal syndrome

Antiandrogens that are currently on the market are particularly useful for the treatment of prostate cancer
during the early stages. However, prostate cancer often progresses to a hormone-refractory state in which
the cancer progresses in the presence of continued androgen ablation or antiandrogen therapy.[9] This
suggests that long term use of these antiandrogens during prostate cancer can lead to the development of
androgen-independent prostate cancer cells or the ability of adrenal androgens to support tumor growth.[8]
This phenomenon is called antiandrogen withdrawal syndrome (AWS) and is one of the major drawbacks
of existing antiandrogens. AWS is defined as tumor regression or symptomatic relief observed upon
discontinuation of the antiandrogen therapy. The mechanism for this is not fully understood but current
theories include alterations of the AR gene, coregulator proteins and/or signal transduction pathways. This
antiandrogen resistance may also be linked to the relative weakness of current antiandrogens as they have
an affinity 50 times or more lower than that of DHT for the AR. This may also explain why compensatory
AR overexpression is often observed.[7]

Androgen receptor gene mutations

AR gene mutations in the LBD that alter ligand specificity and/or functional activity exist and are thought
to contribute to the conversion of some AR antagonists into agonists, which explains the paradoxical
temporary improvement sometimes observed in patients when antiandrogen therapy is stopped.[15] These
mutations can have great effect on the antagonist activities of current small molecule antiandrogens and
make them less efficient in blocking AR function via indirect modulation from inside of the LBP. Recent
studies with circulating tumor cells, suggest that the mutation frequency is higher than previously assumed
based on tumor biopsies.[16] The T877A,[17] W741L and W741C mutations [18] are examples of known
AR LBD mutations. The LNCaP prostate cancer cell line expresses AR with a T877A point mutation that
causes proliferation in the presence of the antiandrogens hydroxyflutamide and cyproterone acetate. This
mutation has also been discovered in patients with antiandrogen withdrawal syndrome being treated with
these compounds.[17] In another study, bicalutamide treatment of LNCaP cells resulted in two LBD
mutations, W741L and W741C,[18] causing bicalutamide to acquire agonist activity to both mutant
ARs.[19] The W741L mutation generates additional space such that the sulfonyl-linked phenyl ring of
bicalutamide is accommodated at the location of the missing indole ring of W741.[20] In non-mutant AR,
the presence of the W741 side chain probably forces bicalutamide to protrude out thus precluding the active
position of H12 on the AR receptor. However, hydroxyflutamide worked as an antagonist for W741 mutant
ARs.[18] This concurs with the theory that flutamide and nilutamide antagonize AR through the mechanism
of “passive antagonism”, as they are of a more modest size then bicalutamide.[20] These drugs may
therefore be effective as a second-line therapy for refractory prostate cancer previously treated with
bicalutamide.[18]

Current status

N-Terminal domain antagonists

Antagonists of the N-terminal domain (NTD) of the AR have been proposed to overcome the limitations of
current antiandrogens regarding mutant ARs, by directly blocking AR function from protein surface,
outside of the LBP. This direct blockade is thought to provide a more efficient strategy to avoid or
overcome abnormal AR action during AWS, as well as allowing for more flexibility in structural
modification without the space limitations of the rigid LBP.[8]

Steroid receptors have similarities in gene sequences and protein structures, leading often to functional
crosstalk among steroid receptors. One of the criteria for AR NTD antagonists is to achieve high degree of
specificity for the AR. It is though important to realize that AR specificity does not necessarily translate in
vivo, since NTD antagonists may also interact with protein targets other than AR.[8]

Ligand binding domain as target site

AR activation requires the formation of a functional activation function 2 (AF2) region in AR LBD that
mediates the interactions between AR and various transcription cofactors. Therefore, most of the research
on NTD AR antagonists focuses on peptides that may directly block the AF2 in AR LBD from protein
surface. Even in bound mutant AR, NTD antagonists would be able to block the AF2 function via direct
surface interaction, regardless of the ligand bound.[8]

Research on these NTD antagonists are usually carried out by affinity screening of phage display libraries
that express random peptides containing various signature motifs. ARs seem to have a distinct preference
for ‘FxxLF’ type of binding motifs (where F = phenylalanine, L = leucine, and X = any amino acid
residue), whereas other nuclear receptors have a highly similar binding mechanism for ‘LxxLL’ type of
binding motifs. This provides a unique opportunity for the development of AR-specific peptides.[8]

Even though small molecule antagonists and NTD antagonist targeting AF2 surface differ in binding sites,
they both inhibit AR function by disrupting AF2 function. Therefore, mechanistically, these NTD
antagonists may also be classified as ‘AF2 antagonists’.[8]

N-Terminal domain as target site

Functionally, AR NTD plays the primary role in regulating target gene transcription activation and
mediating various receptor-protein and intra-receptor N-terminal and C-terminal interactions. Therefore,
modulation of NTD function is considered an efficient strategy to target AR action. Among various
functional domains in different nuclear receptors, NTD is the least conserved and so could maybe become
the best target site for NTD antagonists to achieve AR specificity. However the structural features of the
NTD are undetermined due to a high degree of flexibility in its
conformation. Both biochemical and circular dichroism spectroscopy
analysis suggest that AR NTD is highly disordered under native
conditions, making it a difficult target for drug discovery.[8]

In 2008 there were reports of a chlorinated peptide, sintokamide A,

isolated from marine sponges that effectively inhibits AR N-terminal
domain-activated reporter gene transcription, see figure 8.[21] The
evidence presented was not sufficient to support the conclusion that
sintokamide A directly inhibits the function of AR NTD, and the
mechanism of action needs further investigation.[8]

Selective androgen receptor modulators

Figure 8 Sintokamide A
Small molecule antiandrogens that are available today have
undesirable side effects caused by complete, non-selective inhibition of
AR action. To minimize these side effects, a new class of tissue selective androgen receptor modulators
(SARMs) has been proposed as a novel approach for the treatment of prostate cancer. These ligands should
behave as antagonists in the prostate with either no activity or agonist activity in other target tissues, so as to
have little or no effects in the anabolic tissues or central nervous system (CNS). However discovering this
new class of ligands might be challenging because the molecular mechanism of AR action is not well
understood.[8]

Several mechanisms have been proposed to achieve this tissue selectivity of AR ligands. The most
definitive evidence exists for the role of 5-alpha reductase. 5-alpha reductase is only expressed in specific
tissues and could therefore be a unique contributor to tissue selectivity. Specific inhibition of the type 2
enzyme by finasteride blocks the conversion of testosterone to DHT in the prostate.[8]

Several approaches might make use of the potential tissue-specific conversion to develop SARMs,
including:

1. Inactive parent compounds that are activated by type 2 5-alpha reductase in the prostate to
form antiandrogens.
2. AR agonists that are inactivated by type 2 5-alpha reductase in the prostate.
3. AR agonists that are converted to antiandrogens only by type 2 5-alpha reductase in the
prostate.[22]

Other small-molecule antiandrogens

The development status of other small molecule antiandrogens undergoing research in 2011 can be seen in
table 1.
Table 1
Name of Stage of
Structure Company Other information
compound development

Orally active and

Preclinical – more potent than
Roussel-Uclaf no further current small
RU58642
SA developments molecular
since 1998
antiandrogens.[23]

Orally active, strong

antagonistic activity
Ligand in the prostate
LG120907 Preclinical without raising
Pharmaceuticals
plasma levels of LH
and testosterone.[24]

Orally available,
strong antagonistic
activity in the
prostate without
Ligand raising plasma levels
LG105 Preclinical
Pharmaceuticals of LH and
testosterone. Seems
to be more potent
than LG120907.[24]
High binding affinity
to AR. Unlike
bicalutamide, it does
not promote nuclear
Apalutamide translocation and
Medivation Approved impairs both DNA
(Erleada)
binding to androgen
response elements
and recruitment of
coactivators.[25]
High binding affinity
to AR. Unlike
bicalutamide, it does
not promote nuclear
translocation and
impairs both DNA
Enzalutamide binding to androgen
Medivation Approved response elements
(Xtandi)
and recruitment of
coactivators.[25]
Induces tumor cell
apoptosis and has
not agonist
activity.[26]
BMS-641988 Bristol-Myers Phase I Showed increased
Squibb clinical – trial potency compared to
terminated bicalutamide. Phase
I trial was
discontinued
because of an
epileptic seizure in a
patient.[27] Led to
 the findings that
several
antiandrogens
produce off-target
antagonist binding to
GABA-A
receptors.[28]

Completely inhibits
AR-mediated
transactivation and
Chugai proliferation of the
CH5137291 Pharmaceutical Preclinical CRPC xenograft
Co. Ltd. model LNCaP-BC2,
which is
bicalutamide-
resistant.[29][30]

Natural antiandrogens

Atraric acid and N-

butylbenzenesulfonamide are natural
compounds with antiandrogen
properties which have been purified Figure 10 N-
from the bark of the African tree Figure 9 Ataric acid butylbenzenesulfonamide
Pygeum africanum, see figures 9
and 10.[31] In vitro assays have
shown them both to be selective AR agonists and that they inhibit proliferation of several prostate cancer
cell lines. Atraric acid also hinders extracellular matrix invasion and both compounds are able to prevent
androgen-induced nuclear translocation of the AR. More potent derivatives are currently being synthesized
in hope of improving the pharmacological profile of these two compounds.[32]

See also
Discovery and development of 5α-reductase inhibitors

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External links
The androgen receptor gene mutations database world wide web server (http://androgendb.
mcgill.ca/)

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title=Discovery_and_development_of_antiandrogens&oldid=1162625086"