Discovery of Vilaprisan (BAY 1002670): A Highly Potent and Selective Progesterone Receptor Modulator Optimized for Gynecologic Therapies

Article abstract of DOI:10.1002/cmdc.201800487

Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the treatment of such diseases. Steroidal SPRMs, including mifepristone and ulipristal acetate, have proven effective in clinical trials. However, several steroidal SPRMs containing a dimethylamino substituent have been associated with elevated liver enzymes in patients. An earlier drug discovery program identified lonaprisan as a highly selective SPRM that did not show drug-related change in liver enzyme activity. Building on data obtained from that work, here we describe the research program that culminated in the discovery of a novel steroidal SPRM, vilaprisan, which combines an extremely high potency with very favorable drug metabolism and pharmacokinetic properties. Vilaprisan has entered clinical development and is currently undergoing phase 3 clinical trials.

Full text of DOI:10.1002/cmdc.201800487

DOI: 10.1002/cmdc.201800487
Full Papers
Very Important Paper
Discovery of Vilaprisan (BAY 1002670): A Highly Potent
and Selective Progesterone Receptor Modulator Optimized
for Gynecologic Therapies
Carsten Mçller,[b] Wilhelm Bone,[a] Arwed Cleve,[a] Ulrich Klar,[c] Andrea Rotgeri,[a]
Antje Rottmann,[a] Marcus-Hillert Schultze-Mosgau,[a] Andrea Wagenfeld,[a] and
Wolfgang Schwede*[a]
Progesterone plays an important role in the female reproduc-
tive system. However, there is also evidence that gynecologic
disorders/diseases such as uterine fibroids and endometriosis
are progesterone-dependent. Steroidal and non-steroidal selec-
tive progesterone receptor modulators (SPRMs) have shown
potential for the treatment of such diseases. Steroidal SPRMs,
including mifepristone and ulipristal acetate, have proven ef-
fective in clinical trials. However, several steroidal SPRMs con-
taining a dimethylamino substituent have been associated
with elevated liver enzymes in patients. An earlier drug discov-
ery program identified lonaprisan as a highly selective SPRM
that did not show drug-related change in liver enzyme activity.
Building on data obtained from that work, here we describe
the research program that culminated in the discovery of a
novel steroidal SPRM, vilaprisan, which combines an extremely
high potency with very favorable drug metabolism and phar-
macokinetic properties. Vilaprisan has entered clinical develop-
ment and is currently undergoing phase 3 clinical trials.
Introduction
Progesterone is one of the key regulators of female reproduc-
tive functions, such as uterine and mammary gland develop-
ment, ovulation, and decidualization of the endometrium.
During pregnancy, progesterone plays a key role in implanta-
tion and myometrial relaxation. Most of the diverse effects of
progesterone on the female reproductive target tissues are
mediated via the progesterone receptor (PR).[1] Following the
discovery of progesterone in the early 1930s, the identification
of synthetic progesterone analogues has served as a basis for
the development of oral contraceptives.
Scheme 1. Clinically tested progesterone receptor modulators.
species- and tissue-selective manner.[3] Therefore, these com-
pounds are referred to as selective PR modulators (SPRMs).
There is clinical evidence that the onset and progression of
gynecologic disorders/diseases, such as uterine fibroids, endo-
metriosis and breast cancer, are progesterone-dependent.[4]
Therefore, SPRMs appear to be a promising option for the
treatment of such diseases.
In the 1980s, the first PR antagonist, mifepristone (RU 486),
was discovered by the French company Roussel–Uclaf. Mifepri-
stone is a 19-nor-testosterone derivative, which has a 4-(dime-
thylamino)phenyl group at the 11b-position (see Scheme 1).
The 11b-phenyl group was found to be a crucial structural ele-
ment of all potent steroidal PR antagonists.[2] More recently, it
has become evident that mifepristone and other compounds
of this structural class can exhibit partial agonistic activity in a
In addition to its PR antagonistic activity, mifepristone also
shows relatively strong antagonistic effects toward the gluco-
corticoid receptor (GR).[5] For long-term application as for the
treatment of chronic conditions, improvement in selectivity is
considered to be essential. Therefore, substantial effort has
been devoted toward optimizing receptor selectivity of steroi-
dal SPRMs. Several variations of the steroid skeleton have been
studied.
[a] Dr. W. Bone, Dr. A. Cleve, Dr. A. Rotgeri, Dr. A. Rottmann,
Dr. M.-H. Schultze-Mosgau, Dr. A. Wagenfeld, Dr. W. Schwede
Bayer AG, Pharmaceuticals R&D, 13342 Berlin (Germany)
E-mail: wolfgang.schwede@bayer.com
[b] Dr. C. Mçller
Bayer AG, Market Access, 13342 Berlin (Germany)
Onapristone is characterized by inversion of stereochemistry
at C-13 and C-17 compared with mifepristone, and a replace-
ment of the propynyl side chain at C-17 by a 3-hydroxypropyl
group (Scheme 1). This compound shows an improved selec-
tivity toward antiglucocorticoidal effects.[6] Onapristone dem-
onstrated efficacy in phase 2 clinical trials for the treatment of
[c] Dr. U. Klar
Retired, formerly at Bayer AG, Pharmaceuticals R&D, 13342 Berlin (Germa-
ny)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/cmdc.201800487.
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advanced breast cancer. However, clinical development was
terminated as some patients experienced liver enzyme abnor-
malities.[4f] Elevated levels of liver enzymes have also been ob-
served for mifepristone, ulipristal acetate and proellex (CDB-
4124).[7] All of these compounds have the 4-(dimethylamino)-
phenyl group in common. This structural element is accessible
to metabolic demethylations, which may lead to the formation
of aniline metabolites that have been reported to cause unde-
sired effects in the liver by the formation of reactive intermedi-
ates.[8] The hitherto available data from clinical studies with
SPRMs lacking the dimethylamino phenyl group, for example,
lonaprisan, have provided no evidence of a clinically relevant,
drug-related change in liver enzyme activity.
tion was observed in some patients for a clinically useful
period, the study did not meet its primary endpoint and was
therefore terminated.[13]
The failure of lonaprisan in this clinical oncology trial was a
serious setback for the compound class of steroidal SPRMs for
the treatment of hormone-dependent cancer. However, the
potential of steroidal SPRMs for the treatment of uterine fib-
roids and endometriosis has been demonstrated in several clin-
ical trials with different compounds, including mifepristone, uli-
pristal acetate, asoprisnil, and proellex (CDB-4124). Develop-
ment work on these and other steroidal SPRMs, both for clini-
cal indications and as discovery leads, has continued. Ulipristal
acetate (ESMYATM), for example, is now indicated for pre-surgi-
cal treatment and repeated intermittent treatment of uterine
fibroids in the EU and several other countries.[14]
Investigations have shown that replacement of the dimethy-
lamino group by an acetyl group was tolerated without losing
efficacy. However, the 17a side chain was identified as the key
factor for selectivity toward other nuclear hormone receptors.
This position was therefore chosen for a detailed structure–ac-
tivity relationship (SAR) analysis to help identify highly potent
SPRMs with further decreased endocrine side effects. As a
result of an intensive discovery program, lonaprisan (BAY
865044/ZK 230211), which exhibits a unique potency and se-
lectivity, was identified in the late 1990s. Lonaprisan has a 4-
acetylphenyl substituent at C-11 and a pentafluoroethyl group
as a new 17a side chain (Scheme 1).[9] The compound has
demonstrated much stronger antiproliferative activity[10] than
mifepristone and onapristone in hormone-dependent in vitro
systems. Lonaprisan has also shown superior antitumor activity
in a number of preclinical in vivo models compared with mife-
pristone and onapristone.[11] In two randomized, placebo-con-
trolled, phase 1 studies in healthy postmenopausal women, lo-
naprisan was well tolerated without any sign of elevated liver
enzyme levels, indicating that potential hepatotoxicity was not
a concern with this drug.[12] The efficacy of lonaprisan as
second-line endocrine therapy was evaluated in a randomized,
phase 2 study of postmenopausal women with stage IV, PR-
positive metastatic breast cancer. Although disease stabiliza-
Lonaprisan was also considered to be a potential candidate
for gynecologic indications, due to its very high potency in
combination with its favorable selectivity profile. Three major
metabolites of lonaprisan formed by the biodegradation of the
4-acetyl group were identified in human plasma. These metab-
olites significantly contribute to the overall activity of the drug
candidate (Table 1), as measured by receptor transactivation
assays. The presence of pharmacodynamically active metabo-
lites— in particular, those with long half-lives and thus pro-
longed circulation in vivo— is considered to be disadvanta-
geous in intermittent treatment regimens. Such intermittent
treatment regimens are currently being developed for SPRMs
in long-term use.[15] Accordingly, lonaprisan is not considered
to be an ideal candidate for the treatment of uterine fibroids
and endometriosis.
On the other hand, the surprisingly high potency of some of
the metabolites— in particular, compound 1— showed that
higher polarity is tolerated at the 4-position of the 11b-phenyl
group than originally anticipated. Furthermore, the lonaprisan
metabolite 1 was found to be about seven times less potent
than the parent compound in transactivation assays, although
only a threefold higher dose was required for early pregnancy
Table 1. In vitro activity and metabolic stability in liver microsomes of lonaprisan and its human metabolites.
Compound
Y
PR transactivation assay
Metabolic stability assay
IC50 [nm][a]
Efficacy [%]
Fmax Human [%][a]
Fmax Rat [%][a]
lonaprisan
0.02
0.14
0.10
3.3
100
77
58
50
68
83
metabolite 1
metabolite 2
metabolite 3
100
100
100
81
57
82
[a] Concentration of drug resulting in 50% inhibition. [b] Maximum oral bioavailability calculated from in vitro hepatic extraction ratio (EH) in liver micro-
somes, assuming 100% absorption (Fmax =1ÀEH); see the Experimental Section for details.
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termination tests in rats to achieve a similar efficacy as ob-
served for lonaprisan. This indicates an improved oral bioavail-
ability due to the more favorable physicochemical properties
of metabolite 1 (compound 1 exhibits a 10-fold higher aqueous
solubility compared with the parent compound lonaprisan).
Based on these results, a new drug discovery program was
initiated aiming to identify compounds with potency and se-
lectivity similar to those of lonaprisan, but with higher meta-
bolic stability to avoid the formation of active circulating me-
tabolites.
Introduction of a vinyl group at the 4-position (compound
5) led to almost complete antagonistic efficacy and a signifi-
cant improvement in potency compared with the unsubstitut-
ed derivative (compound 4).
A further increase of the size of the 4-substituent resulted in
some compounds, such as derivatives 6–8, that exhibited full
antagonistic efficacy in vitro. However, as these derivatives
showed lower metabolic stability in liver microsomes, they
were not tested further in vivo.
The pharmacologic activity determined for the lonaprisan
metabolites showed that a certain polarity was tolerated at the
4-position. Thus, several functional groups were introduced at
different distances to the steroid skeleton to systematically ex-
plore the SAR. Derivatives with hydroxy groups, such as the lo-
naprisan metabolite 2, in general exhibited high potency
(Table 1). However, only low metabolic stability was observed
for these compounds.
Results and Discussion
Discovery of vilaprisan
Because the 17a-pentafluoroethyl group demonstrated a fa-
vorable selectivity profile, this position was left unchanged. In-
stead, the new program focused on modifications of the 4-
substituent attached to the 11b-phenyl ring, which was found
to be metabolically unstable in lonaprisan. Broad modifications
of position 17 have been described in the literature and even
the steroid skeleton has been reported with several varia-
tions,[6,16] whereas only a relatively low number of 4-substitu-
ents have been characterized in detail. Until the start of our
new program, only three different substituents at the 4-posi-
tion of the 11b-phenyl ring had been included in the structure
of clinical candidates. Excluding lonaprisan (4-acetyl) and aso-
prisnil (4-hydroxyiminomethyl), another representative of this
compound class,[16] all other SPRMs that entered clinical trials
carried the 4-dimethylamino group. Our new study included
the investigation of a broad range of other groups of com-
pounds. Beyond the variation of 4-substituent of the 11b-
phenyl ring described in this paper, we also explored the influ-
ence of substituents at other positions of the phenyl ring in-
cluding disubstituted compounds. All these derivatives were
found to be not superior compared with the para-substituted
derivatives.
Introduction of a carboxylic acid function at the same posi-
tion (compound 9) led to an almost complete loss of activity.
Addition of a carboxylic acid was further studied by the intro-
duction of a broad range of spacers of different lengths be-
tween the carboxy group and the 11b-phenyl group, such as
in compounds 10 and 11. These compounds yielded variable
results. For example, the acid 10 did not show any improve-
ment in potency. By contrast, the biphenyl derivative 11 was
unexpectedly found to be very potent. In addition, compound
11 exhibited very high metabolic stability in both rat and
human liver microsomes. Therefore, this compound was select-
ed for in vivo characterization.
Replacement of the carboxylic acid in compound 9 by small
amides led to an improvement in potency (for example, in
compounds 12 and 13), showing IC50 values of around 1 nm,
although they did not reach the IC50 values of the most potent
derivatives. To further explore the SAR of amide derivatives, we
synthesized a library of such compounds, including examples
with one or more additional functional groups in the amino
part. Some of these more complex amides showed improve-
ments in potency, but none of them could fulfill the desired
profile to qualify them for an in-depth characterization due to,
for example, poor metabolic stability.
The new derivatives were tested for their PR antagonistic ac-
tivity in vitro using transactivation assays. However, potency in-
dicated in transactivation assays cannot be directly translated
to in vivo efficacy without consideration of the absorption, dis-
tribution, metabolism, excretion properties that are relevant to
achieve the required exposure of the compound in vivo. There-
fore, we decided to consider all compounds for in vivo charac-
terization in a pharmacologic animal model, which had both
an IC50 value of 0.5 nm or lower and showed sufficient in vitro
metabolic stability when tested in human and rat liver micro-
somes.
The dimethylamino group at position 4 of the phenyl ring,
originally discovered in mifepristone, is one of the most promi-
nent substituents for SPRMs at this position. This functional
group is metabolized to aniline-like derivatives which may be
responsible for the hepatotoxicity observed in humans at
higher doses with various SPRMs.[4f,7,8] Accordingly, options to
shift the amino function away from the phenyl ring to avoid
the metabolic formation of aniline derivatives were evaluated
and a library of such compounds was generated by parallel
synthesis. The potency of these compounds was compared
with the dimethylamino derivative 14, illustrated in Table 3.
Surprisingly, and in contrast to other series with different 17-
substituents than pentafluoroethyl, it was observed that re-
placement of the acetyl group in lonaprisan by a dimethylami-
no function led to a 25-fold decrease in potency. Introduction
of a methylene group between the dimethylamino group and
the phenyl group (compound 15) led to a further decrease in
As shown in Table 2, initially the 4-unsubstituted derivative 4
was synthesized and characterized in vitro. This compound
was found to be relatively potent in vitro (IC50 =0.17 nm), but
interestingly showed only 90% efficacy. Earlier observations
from our previous program (unpublished results) indicated
that full inhibitory efficacy was required in the transactivation
assay for compounds to show antagonistic effects in vivo.
Compounds that reached only 90% antagonistic efficacy in
vitro were found to be full PR agonists in vivo.
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Table 2. Structure–activity relationship exploration and metabolic stability in liver microsomes of alkyl, carboxyl, and carboxamide substituents.
Compound
Y[a]
H
PR transactivation assay
Metabolic stability assay
IC50 [nm]
Efficacy [%]
Fmax Human [%]
Fmax Rat [%]
4
5
0.17
0.01
90
79
31
88
99
54
6
7
0.01
0.05
100
100
28
66
53
61
8
0.04
100
8
47
9
25
14
0.09
99
99
98
n.d.[b]
n.d.[b]
10
n.d.[b]
11
100
97
97
12
13
0.90
1.4
100
99
75
39
95
60
[a] Substituent at the 4’ position of the 11b-phenyl ring. [b] Not determined.
Table 3. Structure–activity relationship exploration and metabolic stability in liver microsomes of amines and sulfur-substituted compounds.
Compound
Y
PR transactivation assay
Metabolic stability assay
IC50 [nm]
Efficacy [%]
Fmax Human [%]
Fmax Rat [%]
14
15
16
0.50
8.0
100
100
100
n.d.
98
n.d.
100
3.5
57
88
17
0.01
0.09
100
100
31
94
34
87
18 (vilaprisan)
19
0.9
100
75
69
potency by a factor of more than 15. Compound 16, with a
methyl piperazine at the benzylic position, and several other
derivatives that are not shown here, exhibited potencies that
did not qualify them for in vivo characterization. Other com-
pounds in this series exhibited an improvement in potency
without overcoming the unfavorable pharmacokinetic (PK)
properties.
Derivatives with sulfur-containing substituents at the 4-posi-
tion of the 11b-phenyl ring were also synthesized, three of
which are shown at the bottom of Table 3. The methylsulfide
derivative 17 exhibited high potency in the transactivation
assay but showed only low metabolic stability, probably due to
oxidation at the sulfur atom. Therefore, the sulfone 18 was
synthesized. This compound was slightly less potent in the
transactivation assay than lonaprisan, but demonstrated high
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metabolic stability in human and rat liver microsomes. There-
fore, compound 18, later named vilaprisan, was selected for in
vivo characterization. The sulfoximine 19 was found to be less
potent by a factor of approximately 10 compared with the sul-
fone and did not fully meet the criteria for further in vivo char-
acterization. However, sulfoximine 19 exhibited an approxi-
mately eightfold improvement in aqueous solubility compared
with sulfone 18 (nephelometry: 74 mgLÀ1[19] versus
9 mgLÀ1[18]). Accordingly, this derivative was also selected for
further in vivo characterization. Other sulfur-containing deriva-
tives (not shown) exhibited properties that made them unsuit-
able for further characterization, for example, inefficient poten-
cy, low metabolic stability or increased lipophilicity.
showed favorable PK properties and activity in the early preg-
nancy test in rats were tested in the McPhail test.
In the early pregnancy test, all compounds were adminis-
tered orally except for compound 11 (which was given subcu-
taneously). The doses and corresponding exposures (area
under the curve [AUC]) required to achieve full efficacy were
compared with that of lonaprisan (Table 4). Compound 1 was
found to require doses approximately three times higher com-
pared with vilaprisan to reach full efficacy in this experiment
(1.5 mgkgÀ1 compared with 0.5 mgkgÀ1), whereas compounds
11, 18 (vilaprisan) and 19 required similar doses to lonaprisan
(0.5 mgkgÀ1). Sulfoximine 19 was partly converted into sulfone
vilaprisan (18) in vivo, comprising one-third of the total expo-
sure of the parent compound. This finding suggests that after
administration of sulfoximine 19, vilaprisan contributes signifi-
cantly to the pharmacologic effect due to its 10-fold higher po-
tency. Accordingly, compound 19 is considered to exert its
high activity, at least in part, as a prodrug of vilaprisan (18).
Compounds 1, 11 and 18 (vilaprisan) were also tested in the
endometrial transformation assay in rabbits (Table 4). Com-
pound 1 again demonstrated approximately three times lower
potency than lonaprisan, whereas vilaprisan (18) and the bi-
phenylcarboxylic acid 11 were shown to be as potent as lonap-
risan. Based on the in vivo results described, vilaprisan (18)
and the biphenylcarboxylic acid 11 were selected as the most
promising follow-up candidates.
Compounds 1 (metabolite of lonaprisan), 11, 18 (vilaprisan)
and 19 were studied in an early pregnancy test in rats
(Table 4), which is a suitable in vivo model to predict PR antag-
onistic activity.[9] Progesterone is essential for an undisturbed
pregnancy in mammals. This biologic principle can be used to
determine PR antagonistic activity of a compound. In this
regard, a PR antagonist competitively blocks the PR in the en-
dometrium, which finally leads to the interruption of an ongo-
ing pregnancy.
Besides maintenance of pregnancy, progesterone is respon-
sible for the glandular differentiation and secretory transforma-
tion of the endometrium. These actions of progesterone were
assessed in juvenile rabbits using the McPhail test, to evaluate
PR agonistic and antagonistic effects.[9] Priming of the rabbit
endometrium with 17b-estradiol followed by the administra-
tion of a PR agonist led to an induction of glandular differen-
tiation. The degree of glandular differentiation was determined
by light microscopy (rating grades 1–4; 1=no glandular differ-
entiation, 4=maximal differentiation). Therefore, after priming
with 17b-estradiol, rabbits were either treated with the test
compounds alone to show potential PR agonistic effects, or to-
gether with the natural hormone progesterone to test the PR
antagonistic effects (inhibition of differentiation induced by
progesterone). Only a limited number of test compounds that
Prediction of human exposure-efficacy and dose
For the two compounds 11 and 18 (vilaprisan), the prediction
of the efficacious human dose was performed based on the
predicted human PK and the exposure-efficacy relationship es-
tablished in the animal models, confirming exposure (AUC) as
the driver of efficacy. The data were corrected by plasma pro-
tein binding in human and animal species. For vilaprisan (18),
prediction of human PK was performed by a single species
scaling approach using the in vivo clearance obtained from
cynomolgus monkeys extrapolated to humans on a body
weight basis. The efficacious exposure during the 24 h dosing
interval at steady state [AUC(0–24 h)ss] in the rat and rabbit
models was 116 mg”hLÀ1 and 126 mg”hLÀ1, respectively,
translating into a predicted efficacious human daily oral dose
of 2.5 mg, considering free fraction in human, rat and rabbit
plasma of 5% in all species. For compound 11, prediction of
human PK was performed by a single species scaling using in
vivo clearance from the rat combined with a direct scaling ap-
proach using in vitro clearance from rat and human liver mi-
crosomes. Considering free fractions of 0.6% in human plasma
and 0.7% in rat plasma and the efficacious AUC(0–24 h)ss in
rats of 573 mg”hLÀ1, this translated into a predicted efficacious
human daily oral dose of 11 mg.
Table 4. Activity of selected compounds in vivo.
PR antagonist
Dose of full efficacy
Application route[a]
Termination of early pregnancy in rats (n=6)[b]
lonaprisan
compound 1
compound 11
compound 18 (vilaprisan)
compound 19
0.5 mgkgÀ1
1.5 mgkgÀ1
0.5 mgkgÀ1
0.5 mgkgÀ1
0.5 mgkgÀ1
p.o.
p.o.
s.c.
p.o.
p.o.
Endometrial transformation in rabbits (n=5)[c]
lonaprisan
compound 1
compound 11
compound 18 (vilaprisan)
1.0 mgkgÀ1
3.0 mgkgÀ1
1.0 mgkgÀ1
1.0 mgkgÀ1
p.o.
p.o.
p.o.
p.o.
The significantly lower human daily dose predicted for vilap-
risan (18) compared with compound 11 supported the selec-
tion of vilaprisan (18) as a candidate for further development.
A comparison of vilaprisan (18) with the previous clinical can-
didate lonaprisan in terms of drug metabolism and PK in
humans is briefly summarized below.
[a] p.o.: per os; s.c.: subcutaneous. [b] Full efficacy in termination of early
pregnancy studies means that all animals of the corresponding dose
group lack implantations or have pathologic nidation sites. [c] Full inhibi-
tory efficacy in endometrial transformations studies means that the
degree of glandular differentiation in all animals of the corresponding
dose group was characterized by a McPhail index of 1 or 1.5.
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Drug metabolism and pharmacokinetics in humans
In vitro and in vivo experiments show that lonaprisan is rapidly
metabolized, with the formation of three major metabolites
(compounds 1, 2, 3) in human plasma (see Table 1). They are
formed by the biodegradation of the 4-acetyl group. The expo-
sure in terms of AUC of each of these metabolites significantly
exceeded the AUC of the parent compound lonaprisan (see
Table 5). The IC50 values of compounds 1 and 2 (see Table 1) in
the in vitro transactivation assay were only 5–7-fold higher
compared with the parent compound lonaprisan. Compounds
1 and 2 were therefore expected to significantly contribute to
the pharmacologic activity of the drug candidate in humans.
The metabolite compound 1 was also found to be highly
active in both in vivo models (see Table 4).
Scheme 2. Vilaprisan and its human plasma metabolites.
Syntheses
The synthesis of lonaprisan was described previously.[9] Key
steps in the synthetic route are the introduction of the 11b-
substituent in a copper-catalyzed Grignard reaction and the in-
troduction of the 17a-(pentafluoroethyl) group in a modified
Gassman procedure.[19]
The principal focus of the current drug discovery project
was the systematic modification of the 11b-substituent. There-
fore, the order of the reactions was modified by introducing
the 17a side chain prior to the 11b-substituent. This strategy
allowed an efficient and broad modification of the 11b-sub-
stituent at the end of the sequence. Only the lonaprisan me-
tabolite 2 was synthesized following the original sequence
using a modified building block for the introduction of the
11b-phenyl group. Introduction of the 17a-pentafluoro ethyl
group[19] into the previously published intermediate 22[20] yield-
ed compound 23, which was used for the introduction of the
11b phenyl group. With one exception (the introduction of the
oxetane building block in compound 8 required special reac-
tion conditions, as outlined in the Supporting Information), all
other 11b-substituents were introduced in a copper-catalyzed
Grignard reaction, leading to the intermediates 24a–l as
shown in Scheme 3. In some cases, the 4-substituent Y’ was al-
ready the final group Y, whereas in other cases additional reac-
tions were needed to build up the final substituent. The deriv-
Table 5. Activity of lonaprisan, vilaprisan, and their metabolites in the in
vitro transactivation assay and the percentage of AUC(0–1) of their me-
tabolites in human plasma.
Compound
PR transactivation
assay IC50 [nm]
% AUC of
parent
lonaprisan
0.02
0.14
0.10
3.3
N/A
1
2
3
285[a]
312[a]
920[a]
18 (vilaprisan)
20
21
0.09
5.3
610
N/A
24[b]
19[b]
[a] Determined by LC–MS after single oral administration of 200 mg lo-
naprisan to humans. [b] Determined by LC–MS after multiple oral admin-
istration of 5 mgdayÀ1 vilaprisan.
In contrast, the unchanged parent compound vilaprisan
(compound 18) was the main component in human plasma.[17]
Only a few minor metabolites formed by the reduction and ox-
idation of the steroid skeleton were identified in human
plasma, each not exceeding 10% of the AUC of total drug-re-
lated compounds. This was a consequence of the modification
of the 4-substituent at the 11b-position, as the 4-sulfonyl
group in vilaprisan was not metabolized. Vilaprisan was metab-
olized by oxidation reactions at different positions of the ste-
roid skeleton and reduction of the carbonyl group in the 3-po-
sition, as well as a combination of both modifications. The two
distinct metabolites of vilaprisan that were identified in human
plasma were formed by reduction in the 3-position (compound
20) and by the combination of reduction and oxidation (com-
pound 21) (see Scheme 2). The AUC of these two metabolites
after multiple oral administrations of 5 mg vilaprisan exhibited
approximately 20% of the AUC of unchanged vilaprisan (see
Table 5). The metabolites 20 and 21 showed approximately a
factor of 60 (compound 20) and a factor >6700 (compound
21) lower potency in vitro in the transactivation assay. Consid-
ering the relatively low potency of the two metabolites and
the low fraction in exposure compared with vilaprisan in
humans,[17] neither metabolite contributes to the in vivo activi-
ty of vilaprisan.
Scheme 3. General synthetic approach: a) C2F5I, MeLi-LiBr, À708C then 08C;
b) phenyl Grignard, cat. CuCl, THF, 08C; for compound 24l: iso-propylmag-
nesium chloride, nBuLi, 3-(4-bromophenyl)-3-methyloxetane, cat. CuCl, THF,
08C; c) acidic cleavage.
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atives 1, 3, 4, 5, 6, 8, 14 and 17 were prepared directly from
the intermediates (24a–e, 24j, 24k, 24l) by an acidic cleavage
of the protecting group(s) and concomitant elimination of the
5a-hydroxy group.
cleavage of the protecting group, and elimination of the 5-hy-
droxy group during work-up.
The synthesis of the biphenylcarboxylic acid 11 is shown in
Scheme 5. Starting with intermediate 24i, the benzyl ether was
cleaved by Pd-catalyzed hydrogenation. The phenol 33 was
transferred into the nonaflate 34. A palladium-catalyzed cou-
pling reaction provided the biphenyl ester 35. Cleavage of the
3-ketal under acidic conditions followed by saponification
yielded compound 11.
As shown in Scheme 4, the synthesis of compounds 7, 9, 10,
12, 13, 15, 16 and 18 required additional modification of the
4-substituent. Cyclopropanation of intermediate 24d yielded
compound 25, which was transferred to compound 7 by acidic
cleavage of the protecting group. Acidic deprotection of inter-
mediate 24 f produced 26, which was used for the preparation
of the carboxylic acid 9. Amide formation of 9 under standard
conditions produced the dimethylamide 13. Cleavage of the
silyl ether and the 3-ketal starting from intermediate 24g pro-
duced compound 27, which was oxidized in two steps to the
carboxylic acid 10. Cleavage of the silyl ether in intermediate
24h with tetrabutylammonium fluoride produced compound
28, which was oxidized in two steps to the carboxylic acid 30
and transferred into the amide 32 in two additional standard
steps. Again, acidic cleavage yielded compound 12. The alde-
hyde 26, which was described above, could also be used for
the synthesis of compounds 15 and 16 by reductive amination.
Finally, vilaprisan (18) could be obtained directly from the 3-
protected sulfide 24k by oxidation with Oxoneꢁ, concomitant
Scheme 5. Synthesis of the biphenylcarboxylic acid 11: a) ammonium for-
mate, Pd/C, methanol, RT; b) C4F9SO2F, nBuLi, THF, 08C; c) [4-(methoxycarbo-
nyl)phenyl]boronic acid, Pd(PPh3)4, toluene/ethanol, reflux; d) acetic acid,
358C; e) LiOH, THF, 908C.
The sulfoximine 19 as mixture of epimers was synthesized
according to Scheme 6. Treatment of intermediate 24k with
chloramine-T trihydrateꢁ yielded compound 36, which was oxi-
dized to 37 by treatment with hydrogen peroxide. Cleavage of
the ketal under standard conditions gave compound 38. The
release of the sulfoximine 19 required stronger acidic condi-
tions and was achieved by treatment with concentrated sulfu-
ric acid.
Scheme 6. Synthesis of sulfoximine 19 as a mixture of epimers: a) chlora-
mine-T trihydrate, RT; b) H2O2, ethanol, CH3CN, RT; c) sulfuric acid, methanol,
RT; d) conc. sulfuric acid, CHCl3, 08C.
Conclusions
The first SPRMs became available more than 25 years ago. His-
torically, this compound class has been considered for a
number of indications with high unmet medical need, such as
uterine fibroids and endometriosis. The chronic nature of these
conditions implicates the requirement for long-term medical
treatment. However, the first SPRMs demonstrated relatively
strong GR antagonistic side effects and therefore were not
Scheme 4. Synthesis of derivatives that require additional modification of Y’:
a) diazomethane, Pd(OAc)2, Et2O, 08C; b) 2n HCl, acetone, RT; c) acetic acid,
358C; d) Jones reagent, 08C; e) TBTU, methylamine, RT; f) TBAF, THF, RT;
g) TPAP, NMO, CH2Cl2, molecular sieves, RT; h) 2-methyl-2-butene, THF,
tBuOH, NaOCl, 08C; i) (trimethylsilyl)diazomethane, THF, RT; j) NH3 in metha-
nol, 858C; k) sulfuric acid, methanol, RT; l) oxone, 08C, m) amine, sodium tri-
acetoxyborohydride, CH2Cl2, RT.
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an Acquity UPLC BEH C18 1.7 50”2.1 mm column, with acetonitrile
and water +0.1% formic acid as eluents at 608C, a flow rate of
0.8 mLminÀ1, an injection volume of 2 mL, with diode-array detec-
tor scan at 210–400 nm, ELSD. All tested compounds were at least
considered to be appropriate for long-term application. The
SPRM onapristone that succeeded in the development, failed
in clinical trials due to unexpected liver intolerance with long-
term use. Later, the SPRM lonaprisan was discovered, which ex-
hibited a favorable selectivity profile and was tolerated without
any signs of liver toxicity. However, investigations into its use
in the treatment of metastatic breast cancer failed as it did not
reach its primary clinical endpoint. In clinical trials, it was
found that lonaprisan formed a cocktail of active metabolites
that significantly contributed to its overall activity. Therefore,
the compound was considered suboptimal for gynecologic in-
dications.
1
95% pure, as determined by H NMR spectroscopy.
1) (5’R,8’S,10’R,13’S,14’S,17’S)-5,5,13’-trimethyl-17’-(pentafluor-
oethyl)-1’,2’,7’,8’,12’,13’,14’,15’,16’,17’-decahydro-6’H-spiro[1,3-
dioxane-2,3’-[5,10]epoxycyclopenta[a]phenanthren]-17’-ol (23):
At À308C, 1,1,1,2,2-pentafluoro-2-iodoethane (116 g, 471.7 mmol)
was condensed. A solution of (5’R,8’S,10’R,13’S,14’S)-5,5,13’-trimeth-
yl-1’,2’,6’,7’,8’,12’,13’,14’,15’,16’-decahydro-17’H-spiro[1,3-dioxane-
2,3’-[5,10]epoxycyclopenta[a]phenanthren]-17’-one
(50 g,
134.2 mmol, synthesis described previously[20]) in 500 mL dry tolu-
ene was added at À708C. A 1.5m solution of methyllithium–lithi-
um bromide complex in diethyl ether (290 mL, 435 mmol) was
added slowly at À708C. Afterward, it was stirred for 1 h at 08C.
The reaction mixture was then poured into saturated aqueous am-
monium chloride solution. The aqueous layer was extracted with
ethyl acetate three times. The combined organic layers were
washed with brine, dried over sodium sulfate, filtered and evapo-
rated. The crude product was dissolved in 80 mL toluene (at 708C).
This was then diluted with 250 mL hexane. The resultant suspen-
sion was stirred for 1 h at 08C and was then filtered and dried in
vacuo. The obtained product (51.57 g, 104.7 mmol, 78% yield) was
used without further purification. 1H NMR (300 MHz, CDCl3): d=
5.90–6.14 (multiplet [m], 1H) 3.60 (doublet [d], J=11.49 Hz, 1H)
3.43–3.50 (m, 1H) 3.33–3.43 (m, 2H) 2.54–2.69 (m, 1H) 2.25–2.44
(m, 2H) 2.05–2.23 (m, 4H) 1.94–2.03 (m, 2H) 1.59–1.89 (m, 6H)
1.31–1.51 (m, 3H) 1.20 (broad signal [br] d, J=3.96 Hz, 1H) 1.05 (s,
3H) 0.93 (s, 3H) 0.85 ppm (s, 3H).
Here, we describe a drug discovery program that focused on
the improvement of the PK properties of lonaprisan. Extensive
modifications were attempted to stabilize the 4-substituent of
the 11b-phenyl ring while maintaining the favorable potency,
selectivity and safety profile of former candidates. Several
potent derivatives were identified and comprehensive charac-
terization of the new derivatives in vitro and, for the most
promising compounds, then in vivo, led to the discovery of vi-
laprisan. This compound combines an extremely high selectivi-
ty toward the PR compared with other nuclear receptors[8d]
with favorable tolerability, and significantly improved PK profile
compared with lonaprisan. After successful profiling in preclini-
cal development, investigations of the compound have pro-
gressed to clinical trials, and phase 1[21,22] and phase 2[23] clinical
trials have been completed. Recently, the compound entered
phase 3 clinical development to examine the efficacy and
safety of vilaprisan in the treatment of symptoms associated
with uterine fibroids— measured by decreases in heavy men-
strual bleeding, reductions in fibroid size, and improvements in
2) General procedure for the introduction of the 11b-phenyl
substituent (derivatives 24a–24k): Dibromomethane (5 mL) was
added to 5 mmol magnesium turnings in 0.5 mL dry tetrahydrofur-
an (to activate the magnesium turnings). A solution of the bromo-
phenyl building block (5.1 mmol) in 6 mL dry tetrahydrofuran was
added to this suspension slowly so that the reaction temperature
did not exceed 558C. The solution was then stirred for 1 h. After
stirring, the reaction mixture was cooled to 08C and 0.15 mmol
copper(I) chloride was added. Stirring was continued for an addi-
tional 15 minutes. Afterward, a solution of 1 mmol of compound
23 in 5 mL dry tetrahydrofuran was added at 08C. The reaction
mixture was allowed to warm up to 238C over a 3 h period and
stirred for additional 10 h at this temperature. The reaction mixture
was then poured into ice-cold saturated aqueous ammonium chlo-
ride solution. After stirring for 30 minutes, it was extracted with
ethyl acetate three times. The combined organic layers were
washed with brine, dried over sodium sulfate, filtered and evapo-
rated. The crude product was purified by chromatography over
silica gel using hexane/ethyl acetate.
health-related quality of life of patients. Additionally,
a
phase 2b study for the treatment of women suffering from en-
dometriosis has been initiated.
Herein we have described a research program that culminat-
ed in the discovery of a novel SPRM with a favorable safety
profile and improved PK properties. Based on its high potency,
high selectivity for the PR, and PK with absence of biologically
active metabolites, vilaprisan represents a SPRM optimized for
long-term, intermittent clinical use in pre-menopausal women.
Experimental Section
Chemistry
Materials and methods: All commercially available starting materi-
als and solvents were purchased and used without further purifica-
tion. Flash column chromatography was performed using pre-
packed flash chromatography columns PF-15-SIHP purchased from
Interchim or KP-Sil purchased from Biotage using a Biotage Isolera
3) General procedure for the cleavage of the protecting groups
in the final step under acidic conditions:
a) Using hydrochloric acid (applied for the preparation of com-
pounds 5–8): 0.14 mmol of the protected precursor was dissolved
in 5 mL acetone. Hydrochloric acid (0.7 mL, 4n) was added and the
reaction mixture was stirred for 1 h at 258C. The reaction mixture
was then poured into saturated aqueous sodium hydrogen carbon-
ate solution. It was extracted with ethyl acetate. The organic layers
were washed with brine and the crude product was purified by
column chromatography.
1
separation system. H NMR spectra were recorded at room temper-
ature on Bruker Avance spectrometers operating at 300 or
400 MHz. NMR signal multiplicities are reported as they appeared,
without considering higher-order effects. Chemical shifts (d) are
given in parts per million (ppm) with the residual solvent signal
used as a reference (CDCl3: singlet [s], 7.26 ppm; [D6]DMSO: quin-
tet, 2.50 ppm). Liquid chromatography mass spectrometry (LC–MS)
spectra were recorded on a Waters Acquity ultra performance
liquid chromatography (UPLC)–MS SQD 3001 spectrometer, using
b) Using diluted sulfuric acid (applied for the preparation of
compounds 1, 2, 3, 4, 12, 14, 17): 0.43 mmol of the protected pre-
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cursor was dissolved in 5 mL methanol. Aqueous sulfuric acid
(5 mL, 50%) was added. The reaction mixture was stirred for 2.5 h
at 258C. The reaction mixture was then poured into saturated
aqueous sodium hydrogen carbonate solution. It was extracted
with ethyl acetate. The organic layers were washed with brine and
the crude product was purified by column chromatography.
as described previously.[9,20] In brief, 5–7 days post-coitum, rats (n=
6) were randomized to receive the test compound in different
doses (s.c. or p.o.) or vehicle (benzylbenzoate/castor oil; 1+4 v/v,
respectively 85 mg polyoxyethylene-(50)-stearate in 100 mL 0.9%
w/v NaCl). Autopsy was performed on Day 9; the absence of im-
plantation sites was assessed as complete interruption of pregnan-
cy and the presence of regressed and/or hemorrhagic implantation
sites were defined as pathologic nidation sites. Full efficacy in ter-
mination of early pregnancy studies indicated that all animals of
the corresponding dose group lacked implantations or had patho-
logic nidation sites.
c) Using acetic acid (applied for the preparation of compound
11): 0.51 mmol of the protected precursor was dissolved in acetic
acid (3 mL, 70%). The reaction mixture was stirred for 2 h at 258C
and for another 2.5 h at 358C. The reaction mixture was then
poured into ice water and stirred for 2 h. The formed precipitate
was filtered and purified by column chromatography.
PR activities of the test compounds on endometrial glands were
tested in juvenile rabbits (900–1300 g). From Days 1 to 4, rabbits
were primed with 5.0 mgkgÀ1 dayÀ1 17b-estradiol (s.c.). In order to
test the anti-progestational activity, animals were randomized (n=
4) to receive 0.2 mgkgÀ1 dayÀ1 progesterone (s.c.) and the test
compound (p.o.) from Days 7 to 10. Progestogenic activity was
tested by the test compound (p.o.) alone. Autopsy was performed
on Day 11. As the parameter for progestogenic (induction of glan-
dular differentiation) or anti-progestational activities (inhibition of
induction of glandular differentiation), the McPhail index (degree
of glandular differentiation) was determined by light microscopy
(rating grades 1–4; 1=no glandular differentiation, 4=maximal
differentiation). Full efficacy in endometrial transformation studies
indicated that the degree of glandular differentiation in all animals
of the corresponding dose group was characterized by a McPhail
index of 1 or 1.5.
4) (11b,17a)-20,20,21,21,21-Pentafluoro-17-hydroxy-11-[4-(meth-
ylsulfonyl)phenyl]-19-norpregna-4,9-dien-3-one (18, vilaprisan):
Compound 24 k (5 g, 8.1 mmol) was dissolved in a mixture of
140 mL tetrahydrofuran and 140 mL methanol. The reaction flask
was put in an ice bath. A solution of 20 g Oxoneꢁ in 94 mL water
was slowly added (the temperature inside the flask increased up to
128C). The reaction mixture was kept in the ice bath and stirred
for 3.5 h. It was then diluted with water and dichloromethane. The
phases were separated and the aqueous layer was extracted with
dichloromethane. The combined organic layers were washed with
brine and the crude product was purified by column chromatogra-
phy. The product (3.8 g, 86%) was obtained as a white solid.
1H NMR (400 MHz, CDCl3) d=7.86 (d, J=8.62 Hz, 2H) 7.41 (d, J=
8.11 Hz, 2H) 5.81 (s, 1H) 4.52 (brd, J=6.84 Hz, 1H) 3.06 (s, 3H)
2.68–2.77 (m, 1H) 2.31–2.65 (m, 8H) 2.20–2.30 (m, 1H) 2.18 (s, 1H)
2.08 (s, 1H) 1.74–1.88 (m, 3H) 1.42–1.56 (m, 2H) 0.53 ppm (s, 3H);
LC–MS (ESI+): tR =1.22 min, m/z 545.2 [M+H]+.
Drug metabolism and pharmacokinetics
Metabolic stability in liver microsomes: The compounds were in-
cubated in human or rat liver microsome suspensions at a final
concentration of 0.3–3 mm. The incubations were stopped after 1 h
and analyzed by high-performance liquid chromatography using
MS/MS or ultraviolet detection to determine the rate of degrada-
tion. This provided the in vitro intrinsic clearance according to Lau
et al.[24] based on the amount of microsomal protein and specific
liver weight. Predicted in vivo clearance (CLH) was calculated based
on the “well-stirred” liver model based on rat or human liver blood
flow (QH) resulting in the hepatic extraction ratio EH according to
EH =CLH/QH. Maximum bioavailability (Fmax [%]) was calculated from
the calculated extraction ratio according to: Fmax [%]=1ÀEH assum-
ing 100% absorption.
Pharmacology
PR transactivation assay: The transactivation assay was carried
out in SK-N-MC cells transfected with human PR-B (pRChPR-B-neo)
and the mouse mammary tumor virus promotor linked to the luci-
ferase reporter gene. Cells were grown for 24 h either in the ab-
sence (negative control) or presence of increasing concentrations
of the test compound (0.01 nmolLÀ1 to 1 mmolLÀ1). For the deter-
mination of antagonistic activity, cells were treated with
0.1 nmolLÀ1 promegestone, as well as with increasing concentra-
tions of the test compound (0.01 nmolLÀ1 to 1 mmolLÀ1). Mifepri-
stone was used as the positive control.
Plasma protein binding: Determination of plasma protein binding
of test compounds in human and animal plasma was performed
according to Schuhmacher et al.[25]
In vivo assays
Animals: Rats and rabbits were obtained from Charles River (Ger-
many). Wistar rats (100–230 g) and New Zealand white rabbits (35–
42 days old, 900–1300 g) had access to food and water ad libitum.
All animals were housed according to institutional guidelines at a
12 h/12 h light–dark cycle. Rats were maintained under standard
conditions (20–228C; 50–70% humidity). The rats were housed in
Makrolon cages type IV, five animals per cage, and fed a pelleted
diet (Sniff, Germany). Rabbits were kept at 19Æ18C and 35–65%
humidity. They were conventionally housed in air-conditioned
rooms in Scanbur cages (standard I) and fed Altromin 2023 diet (Al-
tromin, Germany). All animal studies were performed according to
the German Animal Welfare Act and were approved by the compe-
tent regional authorities. All animal studies were performed in ac-
cordance with the ethical guidelines of Bayer AG.
Determination of metabolites of lonaprisan in human serum:
Human serum samples were obtained from volunteers after single
oral administration of 200 mg lonaprisan (clinical study ME301781).
The concentration–time profiles of the three metabolites (com-
pounds 1, 2 and 3) and lonaprisan were determined by an LC–MS/
MS method with external calibration using authentic reference
compounds. The PK parameters of lonaprisan and compounds 1, 2
and 3 were calculated by appropriate methods. The product of hy-
droxylation and reduction in the 11b-position (compound 3) is the
major metabolite of lonaprisan in human serum (AUC=57% of
sum of drug-related compounds or 920% of AUC of lonaprisan).
The exposures of compound 1 (hydroxylation) and compound 2
(reduction) and lonaprisan were found to be 18%, 19% and 6% of
sum of drug-related compounds, respectively. Accordingly, com-
pound 1 and compound 2 exhibited 285% and 312% of the AUC
of lonaprisan.
Test for PR activity during early pregnancy (rat) and endometrial
transformation (rabbit): The early pregnancy test was carried out
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[5] G. Neef, S. Beier, W. Elger, D. Anderson, R. Wiechert, Steroids 1984, 44,
349–372.
Determination of the metabolites of vilaprisan in human
plasma: The exposure of metabolites of vilaprisan (compound 18)
in human plasma was investigated following multiple oral adminis-
tration of 5 mg vilaprisan in healthy volunteers. The concentra-
tion–time profiles and the AUC of the two metabolites (com-
pounds 20, 21) and vilaprisan were determined by a LC–MS/MS
method with external calibration using authentic reference com-
pounds. The PK parameters of vilaprisan and compounds 21 and
22 were calculated by appropriate methods. The parent compound
vilaprisan accounted for the major part of the total drug-related
components in human plasma [AUC(0–24 h)ss ꢀ438 mg”hLÀ1 at
steady state after daily oral administration of 5 mg].
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Metabolite 20, formed by reduction of the 3-keto group resulting
in formation of the 3a-hydroxy derivative, accounted for an
AUC(0–24 h)ss ꢀ97.8 mg”hLÀ1 at steady state after daily oral ad-
ministration of 5 mg vilaprisan corresponding to 22.3% of the
AUC(0–24 h)ss of unchanged vilaprisan. Metabolite 21, formed by
reduction at the 3-keto group and oxidation, accounted for an
AUC(0–24 h)ss ꢀ77.1 mg”hLÀ1 at steady state after daily oral ad-
ministration of 5 mg vilaprisan corresponding to 17.6% of AUC(0–
24 h)ss of unchanged vilaprisan.
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Acknowledgements
Preclinical and clinical studies presented in this manuscript were
funded by Bayer AG.
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Conflict of interest
All authors are current or former employees of Bayer AG.
Keywords: fluorinated ligands · gynecologic therapies
methyl sulfone · selective progesterone receptor modulator ·
structure–activity relationships
·
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