Discovery and in vivo evaluation of potent dual CYP11B2 (aldosterone synthase) and CYP11B1 inhibitors

Article abstract of DOI:10.1021/ml400324c

Aldosterone is a key signaling component of the renin-angiotensin- aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome.

Full text of DOI:10.1021/ml400324c

Letter
pubs.acs.org/acsmedchemlett
Discovery and in Vivo Evaluation of Potent Dual CYP11B2
(Aldosterone Synthase) and CYP11B1 Inhibitors
Erik L. Meredith,*,† Gary Ksander,† Lauren G. Monovich,† Julien P. N. Papillon,† Qian Liu,†
Karl Miranda,† Patrick Morris,† Chang Rao,† Robin Burgis,† Michael Capparelli,† Qi-Ying Hu,†
Alok Singh,† Dean F. Rigel,‡ Arco Y. Jeng,‡ Michael Beil,‡ Fumin Fu,‡ Chii-Whei Hu,‡ and Daniel LaSala‡
†Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, United States
‡Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, United States
S
* Supporting Information
ABSTRACT: Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such
has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone
synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic
target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design
and structure−activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent
inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is
being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing’s syndrome.
KEYWORDS: Inhibitor, CYP11B2, aldosterone synthase, aldosterone, hypertension, enzyme, CYP11B1, Cushing’s syndrome, cortisol
ne of the primary functions of aldosterone through the
Omineralocorticoid receptor (MR) is to effect retention of
sodium and excretion of potassium by the kidney.1 The
elevation of aldosterone causes an increase in blood pressure as
well as facilitating other cardiac, renal, and vascular damage.
Activation of the renin-angiotensin system (RAS) induces
aldosterone production. As such, MR antagonists have been
used in the treatment of heart failure.2−4 While both RAS
inhibitors and MR antagonists have been shown to reduce
some of the pathological effects of aldosterone, there are noted
drawbacks. In the case of RAS inhibition, a reduction of
aldosterone is realized initially; however, this is not
maintained.5,6 Likewise, MR antagonists do not reduce the
level of aldosterone, and in fact, they have been shown to
induce aldosterone production.7 Thus, it was thought that there
would be therapeutic benefit in directly inhibiting aldosterone
production.
Aldosterone is produced in the zona glomerulosa of the
adrenal gland by the enzymatic action of aldosterone synthase
(CYP11B2) on deoxycorticosterone.8,9 Clinical observations
suggested that the racemic aromatase (CYP19) inhibitor
fadrazole affected aldosterone levels and subsequent preclinical
studies demonstrated that the R-enantiomer (FAD286, Figure
1) was a potent inhibitor of CYP11B2.10 From this under-
standing we embarked on a program to investigate the
structure−activity relationship of the FAD286 scaffold and to
gain a more extensive understanding of the potential of
aldosterone synthase inhibition to treat aldosterone-driven
pathologies.
Figure 1. Imidazole derived aldosterone synthase inhibitors.
the outset. Preliminary structure−activity relationships (SAR)
around the phenyl ring indicated that R2 would be a most
promising site for optimization.
In general the compounds from series I (n = 1), series II (n =
2), and series III (n = 3) were prepared as outlined in Scheme
1. Intermediates 3 could be prepared by straightforward
methods from the corresponding starting materials 1a, 1b, or
2. The imidazole intermediates 3 underwent alkylation with the
corresponding substituted benzyl bromide 4 upon heating in
acetonitrile. Full removal and scavenging of the trityl group was
accomplished by treatment with diethylamine and MeOH.
Following alkylation, ring closure for series I and II was readily
possible following removal of the TBS protecting group,
chlorination, and then treatment with potassium tert-butoxide.
The racemic product 6 then underwent separation by chiral
HPLC to afford enantiomers 7 and 8.
In the case of series I, the formation of the saturated ring in a
similar manner to series II and III was problematic as the
corresponding alkyl chloride derivative underwent elimination
Relatively little was known about the impact of substitution
at R1, although we quickly realized that, as with FAD286,
chirality at this point of attachment was important. The impact
of altering the size of the saturated ring was not understood at
Received: August 19, 2013
Accepted: October 10, 2013
© XXXX American Chemical Society
A
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a
Scheme 1. General Synthetic Scheme
a
Reagents and conditions: (a) 1a or 1b, MeOH, HCl. (b) TrCl, Et3N, CH3CN. (c) LiAlH4, THF, 0 °C. (d) TBSCl, imidazole, CH2Cl2. (e) 1a or 1b,
TrCl, pyridine. (f) BH3·THF, THF, 0 °C. (g) Ethanolamine, 90 °C. (h) TBSCl, imidazole, CH2Cl2. (i) 2, TrCl, Et3N, DMF (j) Ph3P+−
CH2CH2CH2OTBS, nBuLi, THF. (k) 5% Pd/C, H2, EtOH. (l) CH3CN, 80 °C; then MeOH/Et2NH, 80 °C. (m) 5b or 5c, 4 M HCl in dioxane, 0
°C. (n) SOCl2. (o) tBuOK, THF. (p) Chiral semiprep HPLC. (q) 5a, NCC(O)OMe, LiHMDS, THF, −78 °C. (r) MsCl, Et3N, CH2Cl2, 0 °C. (s)
NaI, K2CO3, Et3N, DMF, 80 °C. (t) LiOH, THF/H2O (3:2); HCl neutralization. (u) 12, Et3N, DMSO, 100 °C. (v) Oxalyl chloride, cat. DMF,
CH2Cl2; then Et3N, amine, or alcohol.
rather than cyclization. To overcome this problem, the benzylic
position of 5a was activated by the installation of an ester
moiety (10) prior to cyclization. This gave facile conversion to
the desired five-membered ring. Compound 11 could then be
separated by chiral HPLC to give 12 and provide the first data
regarding the tolerance of substitution at R1. Alternatively, the
ester functionality could be removed by hydrolysis followed by
decarboxylation to give 6 (n = 1), which then underwent chiral
HPLC separation to provide the corresponding enantiomers 7
and 8.
Following hydrolysis of ester 11, both amide and ester
derivatives 14 could be prepared by treatment of the carboxylic
acid with oxalyl chloride and then the corresponding amine or
alcohol.
As had been noted with FAD286, chiral separation proved to
be critical as it was shown early on that for the majority of
compounds in all three series (I, II, and III), only one
enantiomer inhibited CYP11B2 activity, while the opposite
enantiomer inhibited CYP19 activity. Some exceptions to this
trend are described below (Table 1).
membered ring analogues (vide supra), the more readily
prepared seven-membered analogues were explored first. In this
case, as was seen with series II, substitution of the phenyl ring
at R2 with a substituted (7d and 7e) or unsubstituted phenyl
ring (7f) provided potent inhibition of CYP11B2. In fact, these
analogues were among the most potent compounds both in
vivo and in vitro, yet they tended to be less selective for other
P450 enzymes. As with series II, a phenyl substituent at R2
allowed for removal of the nitrile without a loss in potency (7d
vs 7e). Encouraged by the tolerance for expansion of ring size,
we pursued additional modifications at the R2 position in series
III. In contrast to series II, nonphenyl substitution with small
groups such as fluorine (7g) or chlorine (7h) were well
tolerated with IC50 values of 42 and 16 nM, respectively. The
methoxy derivative (7i), however, provided much lower
inhibition. More troubling for series III was significant
CYP19 inhibition with both 7g and 7h being >6-fold more
potent than FAD286.
Given that the general SAR for CYP11B2 inhibition thus far
strongly suggested that analogues with a saturated seven-
membered ring were more tolerant of substitution than those
with a six-membered ring, it would be expected that the five-
membered analogues, if they fit the trend, would be less active
than the six. With a reasonable synthesis for the five-membered
analogues now in hand, it was decided to determine if this
indeed was the case.
A number of modifications were made to the R2 position of
series II, and the potency was assessed in an assay measuring
inhibition of aldosterone secretion in NCI-H295R cells.12 The
inclusion of a phenyl group at this position such as 7a (56 nM)
and 7b (37nM) provided good potency. These compounds also
demonstrate that the inclusion of a pheny group at R2 allows
for removal of the nitrile at R3 without loss of activity.
However, much to our surprise, other very simple modifications
at R2 such as fluoro (7c; 87 nM), chloro (6a; 792 nM), methyl
(6b; 464 nM), and methoxy (6c; 390 nM) led to loss in
potency.
As mentioned above, an ester moiety needed to be
incorporated into 5a to facilitate the eventual ring closure.
Following resolution of the enantiomers, the simple chloro-
substituted compound 12a provided good inhibition of
CYP11B2 with IC50 of 17 nM. Unfortunately, 12a also
demonstrated very potent inhibition of CYP19. However, the
surprising tolerance for substitution at R1 in series I encouraged
us to pursue the exploration of the phenyl ring. In contrast to
In parallel with SAR studies on series II, the exploration of
the effect of the saturated ring size on activity was pursued.
Because of the synthetic challenges with forming the five-
B
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ACS Medicinal Chemistry Letters
Letter
chiral separation, was very potent against CYP11B2 (IC50 13
nM). Again, no translation of SAR between the series was
observed, as the direct analogues of 7l in the six-membered
series (6a) had low activity (792 nM), while the seven-
membered analogue (7h) provided similar inhibition (16 nM).
Building on this result, additional R2 analogues were
prepared including methoxy (7m, 5 nM), fluoro (7n, 9 nM),
methyl (7o, 8 nM), and bromo (7p, 10 nM), among others. All
maintained potency against CYP11B2. Equally important was
the fact that several of these analogues had attenuated potency
against CYP19, with 7n inhibiting CYP19 comparable to
FAD286.
Compound 7n was found to have good selectivity against
other P450 isoforms (IC50s: CYP3A 4.8 μM; CYP2D6 >10
μM; CYP2C9 >10 μM). CYP11B1, which is highly
homologous to CYP11B2 and is responsible for cortisol
production, was a notable exception.11 As shown in Table 2,
Table 1. Inhibition of Cellular Aldosterone Production and
Aromatase Enzymatic Function (CYP19)
a
d
CYP19
c
AS
%inh @ 1
μM* or
IC50
cellular
IC50
(nM)
compd
n
R1
R2
R3
(μM)§
FAD286
2
2
2
2
2
2
2
3
3
3
3
3
3
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CN
CN
H
30
56
37
87
792
464
390
1
6§
7a
7b
7c
Ph
Ph
F
CN
CN
CN
CN
CN
H
20*
99*
100*
100*
b
6a
Cl
Me
b
Table 2. Inhibition of Recombinant Human and Rat
CYP11B2 and CYP11B1 Enzyme Activity
6b
b
6c
−OMe
4-F−Ph−
4-F−Ph−
Ph
a
b
a
b
7d
7e
7f
hCYP11B2
rCYP11B2
hCYP11B1
rCYP11B1
compd
IC50 (nM)
IC50 (nM)
IC50 (nM)
IC50 (nM)
2
H
2
FAD286
7d
1.8
0.4
3.2
0.7
0.9
3.8
118
1
9.5
0.3
7.2
2.5
1.5
<0.1
686
0.3
7g
7h
F
CN
CN
CN
CN
42
16
520
17
1.1§
Cl
100*
7g
a
7i
−OMe
Cl
7n
111
24
495
386
12a
12b
12c
14a
−C(O)
0.050§
7o
OMe
14a
1
1
1
−C(O)
−OMe
CN
CN
CN
3
a
See ref 11 for details on protein preparation and enzymatic assay
OMe
b
conditions. Recombinant rat CYP11b2 and CYP11b1 prepared
similarly to the corresponding human enzymes as in ref 11.
−C(O)
F
351
1.5
OMe
4-F-Ph−
CH2−
Cl
95*
45*
O(O)C-
some compounds in this series, such as 14a, demonstrated
greater inhibition of CYP11B1 enzymatic activity than that seen
for CYP11B2. However, compound 7n along with most other
compounds in the series provided modest selectivity over
CYP11B1. On this basis, it was desirable to determine how well
the compounds reduced aldosterone in vivo and to evaluate the
impact of CYP11B1 inhibition.
14b
1
4-F−Ph−
CH2(Me)
N(O)C−
−OMe
CN
5
7j
1
1
1
1
1
1
1
H
H
H
H
H
H
H
Ph
H
441
140
13
5
7k
7l
4-F−Ph−
Cl
H
CN
CN
CN
CN
CN
7m
7n
7o
7p
OMe
F
80*
6§
An efficient pharmacokinetic−pharmacodynamic (PK−PD)
model in Sprague−Dawley (SD) rat was established to enable
rapid compound screening and the development of in vivo SAR
for the CYP11B2 inhibitors.13 Analogous to the cellular assay,
an angiotensin-II (Ang-II) infusion was used to stimulate an
increase in aldosterone production and establish an exper-
imental baseline plasma aldosterone concentration (PAC).
Following oral administration of various CYP11B2 inhibitors
the PAC was measured at given time points. As shown in Table
3, compounds in series I (e.g., 7l and 7n) provided better oral
exposure in general than either series II or III. Compound 7n
provided both good exposure after oral dosing (%F = 42) and
strong reduction of PAC (65%) over the duration of the study.
Compounds 7d, 7g, and 12a provided good reduction in PAC
(66 and 81%, respectively) despite having very low oral
exposure. Given that the cellular and enzymatic potency for
these compounds are in line with the others, the in vivo efficacy
for 7d, 7g, and 12a may be in part due to the generation of
active metabolites.
9
Me
Br
8
87*
47*
10
a
All compounds in the table are single enantiomers except where
noted. With the exception of 7n, the absolute configuration was not
determined. Racemic compound. Aldosterone production assay in
b
c
d
human adrenocortical carcinoma (NCI-H295R) cells. Enzymatic
aromatase (CYP19) assay. See Supporting Information for more detail.
series II, the substitution of R2 with a methoxy (12b) provided
an increase in potency, whereas fluoro substitution (12c)
caused a loss in potency. Additional ester and amide derivatives
such as 14a and 14b were prepared and found to provide good
inhibition of CYP11B2, yet most had an undesirable level of
CYP19 inhibition.
The apparent increase in tolerance for substitution within
series I vs series II and III warranted further exploration of
analogues of type 7. As phenyl substitution at the R2 in both
series II and III provided good potency in vitro and in vivo, we
prepared such analogues in series I. Once again, we observed a
disconnect in the SAR as the corresponding analogues 7j and
7k showed a substantial loss in potency against CYP11B2.
Gratifyingly, 7l, obtained by decarboxylation of 12a followed by
As noted above, one of the key questions was how the
modest in vitro CYP11B2/CYP11B1 selectivity would translate
to an effect on corticosterone levels in vivo. To address this
question, a second PK−PD model in SD rat was developed to
C
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ACS Medicinal Chemistry Letters
Letter
Table 3. Pharmacokinetic−Pharmacodynamic Parameters
AUTHOR INFORMATION
Corresponding Author
*(E.L.M.) Tel: 617-871-7586. Fax: 617-871-7045. E-mail: erik.
meredith@novartis.com.
■
a
for Selected Compounds
dose
TWA [C]
0−8 d
TWA0−8 % reduction of
b
e
f
compd (mg/kg)
(nM)
PAC
%F
b
7d
7f
1
1
1
1
1
1
1
1
1
6
4
1
2
66
4
1
Author Contributions
All authors have given approval to the final version of the
manuscript.
b
b
b
c
27 17
<1
8
7e
152 72
73
69
81
51
65
8
3
1
7
2
g
h
7g
BQL
n.d.
1
Notes
12a
7l
6
2
The authors declare no competing financial interest.
c
152 21
377 27
59
42
18
8
c
7n
7m
14b
ACKNOWLEDGMENTS
b
c
■
33
15
8
8
50 15
35 10
We acknowledge the support of the NIBR Analytical Sciences
group for help in the characterization of the compounds herein.
a
b
Sprague−Dawley rat (n = 3). Compound dosed in corn starch/
c
water. Compound dosed in HCl (1.5 equiv of 1 N/cornstarch/water).
d
ABBREVIATIONS
Time-weighted average (TWA) compound concentration from 0 to 8
■
e
h. TWA % reduction in plasma aldosterone concentration (PAC)
from baseline. Calculated from 0.3 mg/kg i.a. dose. Below
quantitation limit. Not calculated since oral exposure was BQL.
CYP11B2 or AS, aldosterone synthase; CYP11B1, 11β-
hydroxylase; CYP19, aromatase; MR, mineralocorticoid
receptor; RAS, renin-angiotensin system; PAC, plasma
aldosterone concentration; PCC, plasma corticonsterone
concentration; SAR, structure−activity relationship; TWA,
time-weighted average; ACTH, adrenocorticotropic hormone;
PK−PD, pharacokinetic−pharmacodynamic; SD, Sprague−
Dawley; [C], compound concentration
f
g
h
evaluate the effect of 7n on plasma corticosterone concen-
trations (PCC; unlike in humans, corticosterone is the primary
corticosteroid in rats).13 In this model, an increase in baseline
corticosterone level was stimulated with ACTH, followed by
treatment with compound. Although compound 7n showed a
dose-dependent reduction in PCC following ACTH stimula-
tion, the effects on PAC levels were consistently greater on
both a dose and exposure basis.14 On the basis of the ability of
7n to effectively reduce aldosterone levels in vivo and its
generally favorable profile, the compound was selected for
initial human proof-of-concept studies and to understand any
limitations of the potential concurrent cortisol reduction.
In human studies, treatment with 7n was well tolerated and
effective in reducing aldosterone levels to provide sustained
lowering of blood pressure in patients with primary
aldosteronism,15 primary hypertension,16 and resistant hyper-
tension.17 It was found that 7n provided selective reduction of
plasma aldosterone levels without an effect on baseline morning
cortisol levels.15,16 However, suppression of stimulated cortisol
levels was seen at doses above 0.5 mg, which can be attributed
to the modest selectivity for CYP11B2 over CYP11B1.
While the inhibition of cortisol synthesis by 7n has limited its
development to indications where this effect is either desired or
neutral, it provided a valuable initial proof-of-concept for the
ability of a CYP11B2 inhibitor to lower blood pressure in
patients. In addition, the extensive profiling of 7n in
hypertensive patients afforded an opportunistic approach to
safely and effectively lower cortisol levels, which has led to
investigation of the compound as a potential therapy for
Cushing’s syndrome,18 a disease characterized by elevated levels
of cortisol.
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