Novel imidazol-1-ylmethyl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij] quinolin-4-ones as potent and selective cyp11b1 inhibitors for the treatment of cushing's syndrome

Article abstract of DOI:10.1021/jm3003872

CYP11B1 inhibition is a promising therapy for Cushing's syndrome. Starting from etomidate, references I and II, the title compounds were designed and synthesized. Cyclopropyl analogue 4 was identified as a CYP11B1 inhibitor more potent (IC₅₀ = 2.2 nM) than leads and more selective (SF = 11) than I and metyrapone. Since it also showed potent inhibition of rat CYP11B1 and good selectivity over human CYP17 and CYP19, it is a promising candidate for further development.

Full text of DOI:10.1021/jm3003872

Brief Article
pubs.acs.org/jmc
Novel Imidazol-1-ylmethyl Substituted 1,2,5,6-
Tetrahydropyrrolo[3,2,1-ij]quinolin-4-ones as Potent and Selective
CYP11B1 Inhibitors for the Treatment of Cushing’s Syndrome
Lina Yin,†,‡ Simon Lucas,†,∥ Frauke Maurer,§ Uli Kazmaier,§ Qingzhong Hu,*,† and Rolf W. Hartmann*,†
†Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland
(HIPS), Campus C2-3, D-66123 Saarbrucken, Germany
̈
‡ElexoPharm GmbH, Campus A1, D-66123 Saarbrucken, Germany
̈
§Institute fur Organische Chemie, Universitat des Saarlandes, Geb. C4-2, D-66123 Saarbrucken, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: CYP11B1 inhibition is a promising therapy for Cushing’s syndrome. Starting from etomidate, references I and II,
the title compounds were designed and synthesized. Cyclopropyl analogue 4 was identified as a CYP11B1 inhibitor more potent
(IC50 = 2.2 nM) than leads and more selective (SF = 11) than I and metyrapone. Since it also showed potent inhibition of rat
CYP11B1 and good selectivity over human CYP17 and CYP19, it is a promising candidate for further development.
Chart 1. Structures of Ketoconazole, Metyrapone, Letrozole,
and Etomiate and Drug Design Conception
INTRODUCTION
■
Cortisol is a principal human glucocorticoid exhibiting many
important physiological functions. It is involved in the
regulation of the metabolism of proteins, carbohydrates, and
fats; it counteracts insulin, maintains blood pressure and
cardiovascular function, and suppresses the immune system’s
inflammatory response. Cortisol is biosynthesized in the
adrenal cortex with the final conversion from 11-deoxycortisol
catalyzed by steroid 11β-hydroxylase (CYP11B1) (steroido-
gensis cascade is detailed in ref 6c). Normally, the production
and secretion of cortisol are precisely controlled by
adrenocorticotropic hormone within the negative feedback
cycle of hypothalamic−pituitary−adrenal axis. However,
pathological changes in adrenal and the upstream regulating
switches can cause an overproduction of cortisol, which is
known as Cushing’s syndrome (also termed hypercortisolism).
In addition to symptoms like central obesity, headache, and
depression in patients with hypercortisolism, overproduction of
cortisol is associated with hypertension and diabetes mellitus
type II,1 which consequently leads to increased mortality.
CYP11B1 inhibition as the pharmacological approach to
block cortisol biosynthesis is a promising alternative to the
surgical removal of adrenal or pituitary tumors for the
treatment of hypercortisolism. Currently, inhibitors of adrenal
steroidogenesis employed in clinics include ketoconazole,
etomidate, and metyrapone (Chart 1). Among them, the
antifungal agent ketoconazole (inhibiting CYP11B1, CYP11B2,
and CYP17) and the anesthetic etomidate (inhibiting
CYP11B1 and CYP11B2) are used as multiple enzyme
inhibitors. Thus, their use is accompanied by severe side
effects,2 whereas metyrapone is the only drug being reported as
a relatively selective CYP11B1 inhibitor.2 Studies have
demonstrated that metyrapone can effectively reduce cortisol
levels in patients with all types of Cushing’s syndrome.3
However, long-term administration of metyrapone results in
nausea, dizziness, skin rash, edema, acne, and hirsutism.4 This
absence of effective and safe therapy for high cortisol levels
encourages scientists to design novel CYP11B1 inhibitors that
are more potent and selective.
Many reversible CYP inhibitors have been successfully
developed based on a sp2 hybrid nitrogen coordinating to the
heme iron (e.g., inhibitors of CYP11B2,5 CYP17,6 and
CYP197). This mode of action is an important contributor to
high potency, impairing both substrate binding and oxygen
coordinate to the active site. However, the selectivity is a
challenging goal to achieve, especially in the case of CYP11B2,
which is crucial in aldosterone production, because of the high
sequence homology of more than 93% shared between
CYP11B1 and CYP11B2.5c The inhibition of other important
steroidogenic enzymes, such as CYP17 and CYP19, should also
Received: March 22, 2012
Published: July 12, 2012
© 2012 American Chemical Society
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a
be avoided because this would result in a decrease of androgen
or estrogen, respectively, leading to severe undesired effects.
Recently compounds originating from etomidate were reported
by Zolle et al.8a and us9 to be potent CYP11B1 inhibitors.
In the present study, three leads were employed to design
novel inhibitors (Chart 1) including potent CYP11B1 inhibitor
etomidate (IC50 = 0.5 nM 9a) and reference compound I (IC50
= 13 nM), which we have described previously as a CYP11B2
inhibitor,5e and a modest (IC50 = 152 nM) but selective
Scheme 2
(selectivity factor SF = 18 = IC50 CYP11B2/IC50 CYP11B1
)
a
CYP11B1 inhibitor reference compound II.9a The replacement
of phenyl moiety of the etomidate scaffold by tetrahydropyrro-
loquinolinone group from reference I led to a series of
imidazol-1-ylmethyl substituted 1,2,5,6-tetrahydropyrrolo-
[3,2,1-ij]quinolin-4-ones. Not only would this hybrid inherit
the potent inhibition of CYP11B1 but also the replacement of
phenyl by tetrahydropyrroloquinolinone, which is more bulky,
should make the molecule difficult to permeate through the
blood−brain barrier, thereby avoiding undesired anesthetic
effects, which is one of the bioactivities of etomidate. The
introduction of the methylene bridge between the core and N-
containing heterocycle, as present in etomidate and reference
II, was deemed to be advantageous for the selectivity over
CYP11B2, as we have shown in the class of imidazolyl
methylene phenylpyridines.9 In contrast, the ester group from
etomidate was removed because it has been demonstrated to be
deleterious for that selectivity.8b After optimization of the
substituents at the methylene bridge with various functional
groups differing in electronic properties and bulkiness, such as
aliphatic groups, substituted phenyls, and heteroaryls, the
selectivity should be further improved. Besides evaluation of
CYP11B1 inhibition and selectivity toward CYP11B2, selected
potent and selective compounds were further tested for CYP17
and CYP19 inhibition. Furthermore, biological activities of the
enantiomers of 4 were also investigated.
Reagents and conditions: (i) NBS, DMF, 0 °C; (ii) Sn2Bu6,
Pd(PPh3)4, toluene. (iii) Method D: RCOCl, PdCl2(PPh3)2, toluene.
(iv) Method B: NaBH4, MeOH, 0 °C. (v) Method C: imidazole,
SOCl2, THF, room temp.
a
Scheme 3
a
Reagents and conditions: (i) imidazole, SOCl2, CH2Cl2, room temp.
thereafter the introduction of imidazoyl with 1,1′-sulfonyldii-
midazole in THF. The ketone intermediates were prepared via
two different approaches. The introduction of acetyl (1b),
propanoyl (2b), and benzoyl (14b) was accomplisheded with
Friedel−Crafts acylation (Scheme 1). For the other ketones the
core was first brominated with NBS and subsequently reacted
with bis(tributyltin) to afford key intermediate 3c, which was
subsequently coupled with various acyl chlorides to give the
corresponding ketones 3b−5b, 7b−13b, and 15b−16b
(Scheme 2). To abrogate the chiral center, 1b was reacted
with excess 1,1′-sulfonyldiimidazole to yield the vinyl analogue
6 as the minor product and the diimidazolyl 17 as the major
one.
Inhibition of Human CYP11B1 and CYP11B2. The
synthesized compounds were evaluated for their inhibitory
activities in V79 MZh cells expressing human CYP11B1 or
CYP11B2.10 IC50 values are presented in comparison to leads I
and II, etomidate, and another CYP11B1 inhibitor metyrapone
(Table 1).
RESULTS AND DISCUSSIONS
Chemistry. The syntheses of 1−17 are shown in Schemes
1−3. A common synthetic route was exploited for the final
■
a
Scheme 1
Most of the compounds showed strong inhibition of
CYP11B1, with IC50 ranging from 1.4 to 50 nM. It is apparent
that analogues with aliphatic chains substituting at the
methylene bridge (1−6, IC50 < 20 nM) exhibited more potent
inhibition than compounds substituted with aromatic rings (7−
17, IC50 of 13−144 nM). All aliphatic analogues 1−5 showed
IC50 of less than 10 nM except for 1 (IC50 = 17 nM). A trend
can be observed despite of feeble potency difference that as the
bulkiness of aliphatic substituents increased (Me < Et <
cyclopropyl < cyclobutyl < isopropyl),10 the potency of
corresponding compounds increased accordingly. Thus, the
isopropyl 3 turned out to be the most potent CYP11B1
inhibitor in this study, being 10-fold more potent than
metyrapone (IC50 = 15 nM). However, 3 also exhibited strong
inhibition of CYP11B2 (IC50 = 3.8 nM), thereby leading to
poor selectivity (SF = 2.7). In contrast, 4 exceeded metyrapone
in terms of selectivity (SF of 11 and 4.8 for 4 and metyrapone,
respectively) and inhibitory potency (IC50 = 2.2 nM). After the
modification from methyl group to methylidene (6), similar
potency was observed with improved selectivity (SF = 5.3 vs
0.9).
a
Reagents and conditions: (i) pyridine, THF, 0 °C; (ii) AlCl3, 140 °C.
(iii) Method A: RCOCl, AlCl3, CH2Cl2, reflux, then 6 N aq HCl. (iv)
Method B: NaBH4, MeOH, 0 °C. (v) Method C: imidazole, SOCl2,
THF, room temp.
compounds 1−5 and 7−16 (Schemes 1 and 2). The
tetrahydropyrroloquinolinone core 1c, as the common
intermediate, was synthesized from commercially available
2,3-dihydro-1H-indole via N-acylation with 3-chloropropionyl
chloride and subsequent cyclization with AlCl3 under molten
conditions. 1c was subsequently converted into substituted
ketone intermediates, from which the final compounds were
yielded after further reduction using sodium borohydride and
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(IC50 of 2.2 nM vs 152 nM). This can probably be attributed to
the introduction of the methylene bridge between the
tetrahydropyrroloquinolinone core and the N-containing
heterocycle and also probably to the replacement of
isoquinolinyl by imidazolyl.
Table 1. Inhibition of CYP11B1 and CYP11B2 by 1−17
Biological Difference between Enantiomers. To
investigate the possible influence that different configurations
may show on the inhibitory potency, racemic 4 was resolved by
chiral HPLC. It turned out that enantiomer (−)-4 is about 6-
fold more potent than (+)-4 toward CYP11B1 (IC50 of 1.5 nM
vs 10.3 nM), which indicates the presence of a hydrophobic
cavity close to the heme that is large enough to accommodate
the c-propyl group of both configurations. The presence of such
hydrophobic subpockets in both CYP11B isoforms is supported
by pharmacophore and homology models.5
Selectivity against Human CYP17 and CYP19. Since
CYP17 and CYP19 are crucial enzymes involved in androgen
and estrogen biosynthesis, respectively, the selectivities for four
of the most potent and/or selective compounds against these
two enzymes were tested as criteria to evaluate safety (Table 2).
a
IC50 (nM)
b
c
d
compd
R
CYP11B1
CYP11B2
SF
1
2
3
4
Me
Et
17
15
0.9
0.9
2.7
11
6.5
1.4
2.2
10.3
1.5
3.4
19
5.8
3.8
24
i-propyl
c-propyl
(+)-4
(−)-4
5
c-butyl
4.2
100
19
1.2
5.3
0.5
0.6
1.1
0.8
2.6
2.1
6
CH2
7
2-F Ph
40
8
3-F Ph
29
18
9
4-F Ph
27
29
10
3-MeO Ph
4-MeO Ph
3-CN Ph
4-CN Ph
Ph
110
40
88
Table 2. Inhibition of CYP17 and CYP19 by Selected
Compounds
11
104
304
308
33
12
144
70
13
4.4.
0.7
2.4
1.4
1.9
0.02
18
a
b
CYP17
CYP19
c
c
d
e
14
50
compd IC50 (nM) SF over CYP17 IC50 (nM) SF over CYP19
15
2-furanyl
2-thienyl
20
47
3
1550
1107
1309
>260
>125
>500
228
17
>357
104
0.9
16
13
18
4
2880
17
438
13
851
0.2
2768
0.1
72
6
>5000
>5000
I
11
43
1.1
II
152
0.5
15
a
E. coli expressing human CYP17; substrate progesterone, 25 μM;
etomidate
metyrapon
0.5
4.8
b
abiraterone, IC50 = 72 nM. Human placental CYP19; substrate
androstenedione, 500 nM; inhibitor concentration 500 nM; fadrozole
IC50 = 41 nM. Mean value of at least three experiments, standard
deviation less than 10%. IC50 CYP17/IC50 CYP11B1
IC50 CYP11B1
a
c
Mean value of at least three experiments, relative standard deviation
less than 25%. Inhibition curves show no significant difference from
unity. Hamster fibroblasts expressing human CYP11B1. Substrate:
deoxycorticosterone, 100 nM. Hamster fibroblasts expressing human
d
e
.
IC50 CYP19/
b
.
c
d
CYP11B2. Substrate deoxycorticosterone, 100 nM. IC50 CYP11B2
/
IC50 CYP11B1
.
As can be seen, 3 and 4 exhibited weak CYP17 inhibition with
IC50 values over 1500 nM, whereas 6 and 11 were even less
active (IC50 > 5000 nM). Moreover, because of the structural
similarity of the synthesized compounds to the CYP19
inhibitors, like letrozole (Chart 1), the inhibition of CYP19 is
not a surprise. Compounds 6 and 11 showed strong inhibition
with IC50 of 17 and 43 nM (Table 2), respectively. In contrast,
3 and 4 with alkyl groups exhibited only modest inhibition of
CYP19 (IC50 > 200 nM, Table 2) resulting in good selectivity
factors (IC50 CYP19/IC50 CYP11B1) of more than 357 for 3 and 104
for 4.
However, further modification by introducing a phenyl group
onto the methylene bridge (14) led to a slight decrease in
inhibition (IC50 = 50 nM). Moreover, F substitution of the
phenyl ring (7−9) led to a slight improvement of inhibitory
potency (IC50 from 27 to 40 nM) compared to nonsubstituted
14, whereas analogues substituted with MeO or CN (10−13)
exhibited similar or reduced inhibitory activity (IC50 from 40 to
144 nM). Furthermore, the position of the substituents is also a
determinant of inhibitory potency. Analogues with para-
substituted phenyl are more potent than the ones with meta-
substitution, especially for MeO and CN, whereby para-
substituted analogues 11 and 13 (IC50 of 40 and 70 nM,
respectively) are twice as potent as the corresponding meta-
substituted 10 and 12 (IC50 of 110 and 144 nM, respectively).
Interestingly, replacement of the phenyl group by its less
bulky bioisosteres 2-furanyl (15) and 2-thienyl (16) elevated
the inhibition of CYP11B1 to 20 and 13 nM, respectively.
However, analogue 17 with a methyl and an additional
imidazolyl group at the methylene bridge exhibited a dramatic
decrease in inhibitory activity (IC50 = 438 nM).
Inhibition of Rat CYP11B1 Enzyme. Compound 4
showed 91% inhibition of rat CYP11B1 at 2 μM, in comparison
to 31% for reference I. This improvement of rat CYP11B1
inhibition facilitates further evaluation in vivo.
CONCLUSION
■
Starting from three leads (etomidate, references I and II), novel
imidazol-1-ylmethyl substituted 1,2,5,6-tetrahydropyrrolo-
[3,2,1-ij]quinolin-4-ones were designed and synthesized as
potent and selective CYP11B1 inhibitors for the treatment of
Cushing’s syndrome. The replacement of the phenyl ring in the
etomidate scaffold by tetrahydropyrroloquinolinone moiety
from reference I sustained the potent inhibition of CYP11B1,
while it decreased the CYP11B2 inhibition. It has been shown
that the compounds with aliphatic substituents at the
Compound 4 as the most selective one (SF = 11) in this
study is more potent and selective toward CYP11B1 than
parent reference I (SF = 0.02). Although 4 is slightly less
selective than reference II (SF = 18), it is much more potent
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methylene bridge are more potent than phenyl analogues, while
meta-substitution increased inhibition compared to para-
substitution for these phenyl compounds. Furthermore, 4 was
identified as a CYP11B1 inhibitor more potent (IC50 = 2.2 nM)
than leads I and II and more selective (SF = 11) than reference
I and metyrapone. Since 4 also showed improved inhibition of
rat CYP11B1 and good selectivity over CYP17 and CYP19, it is
considered to be a promising candidate for further evaluation in
the rat.
ACKNOWLEDGMENTS
■
The authors thank Dr. Jorg Haupenthal, Dr. Christina Zimmer,
̈
Sabrina Rau, Jeannine Jung, and Jannine Ludwig for performing
the in vitro tests, Thomas Michael for the synthesis of 2, and
Dr. Stefan Boettcher and Michael Zender for the chiral
separation and ee determination. The authors also appreciate
Professor Hermans (University of Maastricht, The Nether-
lands) for providing us with V79MZh11B1 cells expressing
human CYP11B1, and the kind help from Professor Dr. Rolf
Muller (Saarland University, Saarbrucken, Germany) in
determining HRMS.
̈
̈
EXPERIMENTAL SECTION
■
Chemistry. The purities of the final compounds were greater than
95%.
ABBREVIATIONS USED
■
Method C: Introduction of Imidazoyl Moiety. A solution of the
obtained alcohol (1.0 equiv) in dry THF was added to a solution of
thionylbis(imidazole) (prepared previously by reaction of imidazole
(16 equiv) with thionyl chloride (4.0 equiv) in dry THF and filtration
to remove precipitated imidazole hydrochloride) at 0 °C. The mixture
was stirred for 1 h at 0 °C and an additional 18−30 h at ambient
temperature. Water was added and the mixture extracted with ethyl
acetate three times. The combined organic extracts were washed with
water and brine, and the solvent was evaporated in vacuo after drying
over MgSO4. The crude product was purified by flash chromatography
to yield the corresponding product.
8-[Cyclopropyl(1H-imidazol-1-yl)methyl]-1,2,5,6-
tetrahydropyrrolo[3,2,1-ij]quinolin-4-one (4). The title com-
pound was synthesized according to method C using 4a (0.56 g,
2.30 mmol), imidazole (1.88 g, 27.6 mmol), SOCl2 (0.50 mL, 6.90
mmol), and dry THF (20 mL). The crude product was purified by
flash chromatography (MeOH/CH2Cl2, 0 to 1:50) to yield white
crystals (0.50 g, 74%), mp 146−147 °C, Rf = 0.14 (MeOH/CH2Cl2;
1:20). 1H NMR (500 MHz, CDCl3): δ 0.42−0.50 (m, 2H), 0.76−0.85
(m, 2H), 1.46−1.54 (m, 1H), 2.66 (t, J = 7.8 Hz, 2H), 2.93 (t, J = 7.8
Hz, 2H), 3.15 (t, J = 8.5 Hz, 2H), 4.08 (t, J = 8.5 Hz, 2H), 4.30 (d, J =
9.3 Hz, 1H), 6.82 (s, 1H), 6.90 (s, 1H), 6.95 (s, 1H), 7.07 (s, 1H),
7.67 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 4.8, 5.3, 16.6, 24.4, 27.7,
31.5, 45.4, 66.3, 118.3, 120.3, 121.8, 124.1, 129.3, 129.4, 135.6, 136.4,
141.4, 167.5. MS (ESI) m/z = 226 [M − imidazole]+. HRMS (ESI):
calcd for C18H19N3O [M + H]+, 294.1562; found, 294.1558. The
racemate 4 was separated by preparative HPLC on chiral stationary
phase (45% hexane/ethanol, 1.0 mL/min) to yield (+)-4 ([α]2D0 +3.5
(c 1.0, DMSO); 99.6% ee and tR = 19.2 min by analytical HPLC using
30% hexane/ethanol) and (−)-4 ([α]2D0 −4.0 (c 1.0, DMSO); 93.3% ee
and tR = 22.9 min by analytical HPLC using 30% hexane/ethanol).
CYP, cytochrome P450; CYP11B1, 11β-hydroxylase;
CYP11B2, aldosterone synthase; CYP17, 17α-hydroxylase-
17,20-lyase; CYP19, aromatase; SF, selectivity factor; ee,
enantiomeric excess
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■
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and characterization of all intermediates,
HPLC purities of all final compounds, 1H and 13C NMR of 1−
3 and 5−17, resolution of racemate 4, and a description of
biological tests. This material is available free of charge via the
Internet at http://pubs.acs.org.
Negri, M.; Muller-Vieira, U.; Birk, B.; Hartmann, R. W. Overcoming
̈
undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldoster-
one synthase inhibitors: influence of heteroaryl derivatization on
potency and selectivity. J. Med. Chem. 2008, 51, 5064−5074. (e) Lucas,
S.; Negri, M.; Heim, R.; Zimmer, C.; Hartmann, R. W. Fine-tuning the
selectivity of aldosterone synthase inhibitors: structure−activity and
structure−selectivity insights from studies of heteroaryl substituted
1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives. J. Med.
Chem. 2011, 54, 2307−2319.
AUTHOR INFORMATION
■
Corresponding Author
(6) (a) Hu, Q.; Negri, M.; Jahn-Hoffmann, K.; Zhuang, Y.; Olgen, S.;
*For Q.H.: phone, 0049 681 30270326; e-mail, q.hu@mx.uni-
saarland.de. For R.W.H.: phone, +(49) 681 302 70300; fax,
+(49) 681 302 70308; e-mail, rolf.hartmann@helmholtz-hzi.de;
home page, http://www.helmholtz-hzi.de/?id=3897.
Bartels, M.; Muller-Vieira, U.; Lauterbach, T.; Hartmann, R. W.
̈
Synthesis, biological evaluation, and molecular modeling studies of
methylene imidazole substituted biaryls as inhibitors of human 17α-
hydroxylase-17,20-lyase (CYP17)Part II: Core rigidification and
influence of substituents at the methylene bridge. Bioorg. Med. Chem.
2008, 16, 7715−7727. (b) Hu, Q.; Negri, M.; Olgen, S.; Hartmann, R.
W. The role of fluorine substitution in biphenyl methylene imidazole
type CYP17 inhibitors for the treatment of prostate carcinoma.
ChemMedChem 2010, 5, 899−910. (c) Hu, Q.; Jagusch, C.; Hille, U.
E.; Haupenthal, J.; Hartmann, R. W. Replacement of imidazolyl by
Present Address
∥Grunenthal Pharma GmbH, Global Drug Discovery, Ziegler-
̈
strasse 6, D-52078 Aachen, Germany.
Notes
The authors declare no competing financial interest.
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pyridyl in biphenyl methylenes results in selective CYP17 and dual
CYP17/CYP11B1 inhibitors for the treatment of prostate cancer. J.
Med. Chem. 2010, 53, 5749−5758. (d) Hu, Q.; Yin, L.; Jagusch, C.;
Hille, U. E.; Hartmann, R. W. Isopropylidene substitution increases
activity and selectivity of biphenyl methylene 4-pyridine type CYP17
inhibitors. J. Med. Chem. 2010, 53, 5049−5053. (e) Hille, U. E.; Hu,
Q.; Vock, C.; Negri, M.; Bartels, M.; Mueller-Vieira, U.; Lauterbach,
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