Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential treatments for hypertension

Article abstract of DOI:10.1016/j.bmcl.2017.04.021

We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.

Full text of DOI:10.1016/j.bmcl.2017.04.021

Accepted Manuscript
Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential
treatments for hypertension
Scott B. Hoyt, Jerry Taylor, Clare London, Amjad Ali, Feroze Ujjainwalla, Jim
Tata, Mary Struthers, Doris Cully, Tom Wisniewski, Ning Ren, Charlene Bopp,
Andrea Sok, Andreas Verras, Daniel McMasters, Qing Chen, Elaine Tung, Wei
Tang, Gino Salituro, Joe Clemas, Gaochao Zhou, Douglas MacNeil, Ruth Duffy,
Yusheng Xiong
PII:
S0960-894X(17)30384-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.04.021
BMCL 24874
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 December 2016
10 March 2017
6 April 2017
Please cite this article as: Hoyt, S.B., Taylor, J., London, C., Ali, A., Ujjainwalla, F., Tata, J., Struthers, M., Cully,
D., Wisniewski, T., Ren, N., Bopp, C., Sok, A., Verras, A., McMasters, D., Chen, Q., Tung, E., Tang, W., Salituro,
G., Clemas, J., Zhou, G., MacNeil, D., Duffy, R., Xiong, Y., Discovery of indazole aldosterone synthase (CYP11B2)
inhibitors as potential treatments for hypertension, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://
dx.doi.org/10.1016/j.bmcl.2017.04.021
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Discovery of indazole aldosterone synthase
(CYP11B2) inhibitors as potential treatments
for hypertension
Leave this area blank for abstract info.
Scott B. Hoyt,* Jerry Taylor, Clare London, Amjad Ali, Feroze Ujjainwalla, Jim Tata, Mary Struthers, Doris
Cully, Tom Wisniewski,a Ning Ren, Charlene Bopp, Andrea Sok, Andreas Verras, Daniel McMasters, Qing
Chen, Elaine Tung, Wei Tang, Gino Salituro, Joe Clemas, Gaochao Zhou, Douglas MacNeil, Ruth Duffy, and
Yusheng Xiong

Bioorganic & Medicinal Chemistry Letters
Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential
treatments for hypertension
Scott B. Hoyt,*,a Jerry Taylor,a Clare London,a Amjad Ali,a Feroze Ujjainwalla,a Jim Tata,a Mary
Struthers,a Doris Cully,a Tom Wisniewski,a Ning Ren,a Charlene Bopp,a Andrea Sok,a Andreas Verras,a
Daniel McMasters,a Qing Chen,a Elaine Tung,a Wei Tang,a Gino Salituro,a Joe Clemas,a Gaochao Zhou,a
Douglas MacNeil,a Ruth Duffy,a and Yusheng Xionga
aMerck Research Laboratories, PO Box 2000, Rahway, NJ 07065
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of
CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of
CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like
physical and pharmacokinetic properties. On the basis of these and other data, the indazole
series was progressed to lead optimization for further refinement.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Aldosterone synthase
CYP11B2
Indazole
Hit-to-lead
Hypertension
Hypertension is the most common chronic disease, afflicting
nearly 80 million adults in the United States, and >1 billion
people worldwide.1 It is a significant contributing factor to a
majority of heart attacks and strokes, a majority of cases of
coronary heart disease and heart failure, and is known to
contribute to >360,000 deaths each year in the U.S. alone.2
Despite the availability of current treatments, roughly 50% of all
hypertensive patients display resistant hypertension, and are
unable to control their blood pressure to goal, even after
treatment with a cocktail of three or more medications.3 Thus,
while hypertension is sometimes regarded as a disease well-
served by existing treatments, there in fact are at least 40 million
resistant hypertensives in the U.S., and a far greater number
worldwide, who are still in need of more efficacious therapies.
Aldosterone is biosynthesized from steroidal precursors such
as cholesterol and pregnenolone. The final three rate-limiting
steps in its biosynthesis are catalyzed by aldosterone synthase
(CYP11B2). Potent inhibitors of CYP11B2 should effectively
block aldosterone biosynthesis, thereby leading to lower plasma
aldosterone levels, and ultimately to reduced blood pressure.7-17
In a recent Phase II clinical trial, the CYP11B2 inhibitor LCI-699
effectively reduced plasma aldosterone levels as well as systolic
and diastolic blood pressure, thus providing clinical validation
for this approach.18,19
CYP11B2 has a close structural homolog in CYP11B1, an
enzyme that catalyzes the formation of cortisol. Given the
physiological importance of cortisol in glucose metabolism and
stress response, as well as the high homology (>93%) between
the two targets, selectivity for inhibition of CYP11B2 vs.
CYP11B1 is both required, and potentially challenging to attain.
In cell-based in vitro assays, LCI-699 displays ~4-fold selectivity
for inhibition of CYP11B2 vs. CYP11B1.14 In the clinic, doses
of LCI-699 that effectively lower blood pressure also evoke an
undesired impairment of the stress response, presumably as a
consequence of CYP11B1 inhibition.18 CYP11B2 inhibitors that
display higher levels of selectivity than LCI-699 are thus desired
as treatments for hypertension.
Many of the most commonly prescribed antihypertensive
agents inhibit steps in the Renin-Angiotensin-Aldosterone
System (RAAS). This cascade begins with the peptide precursor
angiotensinogen, which can be processed sequentially by the
enzymes renin and ACE (angiotensin converting enzyme) to give
angiotensin II. Binding of angiotensin II to the angiotensin
receptor then stimulates the release of aldosterone, a steroid
hormone that elevates blood pressure by promoting
vasoconstriction, sodium and water retention, and increased
central sympathetic drive.4-6
———
* Corresponding author. Tel.: +1-201-344-4535; e-mail: scott.hoyt@alumni.upenn.edu.

Though less homologous to CYP11B2, the related steroidal
CYPs 17, 19 and 21 catalyze the formation of important
hormones such as estrone and testosterone. Selectivity versus
these targets, as well as the major hepatic CYPs, is also required.
CYP11B2, selectivity vs. CYP11B1, and low intrinsic clearance
in rat liver microsomes, thus providing initial proof of concept
for the indazole design. Substitution of the pyridyl 3-position
with a small electron-withdrawing group such as fluorine
(compound 2) reduced potency, possibly by weakening the
interaction between the pyridine nitrogen and the CYP heme. In
contrast, incorporation of trifluoromethyl or methyl ester at the 3-
position (compounds 3 and 4) produced modest increases in
potency, perhaps as a result of beneficial lipophilic or hydrogen
bonding interactions that outweighed any deleterious electronic
effects. Electron-donating groups such as methoxy (compound
5) or various tertiary alcohols (compounds 6 and 7) increased
potency further, with the racemic analog 7 displaying a >100-fold
improvement in CYP11B2 inhibition relative to parent 1. The
tertiary alcohols also tended to impart improved aqueous
solubility (data not shown) and clearance properties (see Tables 3
and 7), and thus were incorporated in subsequent designs.
Our goal is to discover selective CYP11B2 inhibitors as
treatments for resistant hypertension. Our team had previously
identified a benzimidazole lead series that displayed promising
properties, including robust aldosterone-lowering efficacy in
rhesus monkeys.9 Structural modifications to the benzimidazoles
have led to the subsequent discovery of imidazopyridine,
pyrazolopyridine, triazolopyridine, and indazole lead series.20-23
Of these, the indazoles incorporate the most significant design
change, as they alter the connectivity between the bicyclic core
and the pyridyl heme-binding domain, and thus may significantly
change the way the core is displayed within the binding pocket.
Hit-to-lead efforts, described herein, have produced benchmark
indazoles that display potent inhibition of CYP11B2, high
selectivity versus homologous steroidal CYPs and major hepatic
CYPs, and lead-like physical and pharmacokinetic properties.
Table 2. Effect of indazole 3-substitution on hCYP11B2 and
hCYP11B1 potency and selectivity
Compounds were synthesized as described in the
Supplementary Information section, and were tested in cell-based
assays for inhibition of human CYP11B2 and CYP11B1. The
preparation of these compounds has also been described
previously.23
Table 1. Effect of pyridine substitution on hCYP11B2 and
hCYP11B1 potency and selectivity
Cpd
R1
R2
R3
CYP11B2a CYP11B1a B1/B2b
(IC50, nM)
(IC50, nM)
540
8
H
CH3
CH3
CH3
CH3
CH3
CF3
CH3
CF3
CH3
CH3
CH3
CH3
CH3
CH3
CF3
15
36
9
CH3
OCH3
CF3
c-Pr
CH3
CH3
CF3
34
780
44
10
11
12
13
14
15
25
1400
>8300
>8300
340
57
300
760
14
>27
>11
24
R
CYP11B2a CYP11B1a B1/B2b Rat Mic
Cpd
c
Clint
(IC50, nM)
220
(IC50, nM)
>8300
H
>38
>18
19
43
1
2
3
4
5
6
7
33
390
12
CH3
77
860
11
F
460
88
31
44
11
>8300
1700
520
85
aAssay details reported in Supplementary Information.
CF3
300
n.d.
n.d.
n.d.
230
bRatio of hCYP11B1 IC50 / hCYP11B2 IC50.
CO2CH3
OCH3
C(CH3)2OH
17
With optimized pyridine substituents in hand, we next
examined the impact of substitution at the indazole 3-position.
These studies indicated that small groups were strongly preferred
at C3. As shown in Table 2, the parent, unsubstituted compound
in this series (analog 8) displayed potent and moderately
selective inhibition of CYP11B2. Substitution of C3 with
smaller groups such as methyl or methoxy afforded analogs
(compounds 9 and 10) that were equivalent to 8 in terms of
potency and B1/B2 selectivity. If the size of the C3 group
increased even slightly beyond that, however, potency decreased
dramatically. Thus, substitution with a slightly larger electron-
withdrawing substituent (CF3, compound 11) or electron-
donating substituent (c-Pr, compound 12) resulted in 20 – 50x
decreases in CYP11B2 inhibitory potency relative to parent 8.
These results stand in marked contrast to those obtained in the
benzimidazole series, where a cyclopropyl at the 1-position
provided optimal potency, and suggest that the indazole bicycle
binds CYP11B2 differently than the benzimidazole.9
1300
210
30
19
C(CH3)(CF3)OH 2.0
47
24
aAssay details reported in Supplementary Information.
bRatio of hCYP11B1 IC50 / hCYP11B2 IC50.
cIntrinsic clearance in rat liver microsomes (mL/min/kg).
We began by examining substitution on the key pyridine
moiety, the putative heme-binding domain in these compounds.
Prior work in the benzimidazole series had shown the pyridine to
be essential for potent CYP11B2 inhibition, and had indicated
that substitution at the pyridine 2- or 6-positions was not
tolerated, as it presumably interfered with coordination to the
CYP heme. We thus focused our efforts on the pyridyl 3-
position, a site that had tolerated significant substitution in prior
work. As shown in Table 1, the parent compound in this series
(compound 1, R = H) displayed moderately potent inhibition of
Analogs 8 – 12 were prepared in the gem-dimethyl tertiary
alcohol series. As conversion of one methyl group to a

trifluoromethyl had been shown to improve potency (Table 1,
compounds and 7), we prepared the (S)- and (R)-
trifluoromethyl or cyano (compounds 24 and 25), all resulted in
diminished CYP11B2 inhibition. Finally, at C4 a variety of
substituents were tolerated (compounds 26 – 28), and when
optimal substituents from C4 and C7 were combined, the
resulting disubstituted analogs (compounds 29 and 30) inhibited
CYP11B2 with IC50s in the sub-nanomolar range.
6
trifluoromethylated analogs 13 and 14. The (S)-trifluoromethyl
enantiomer 13 displayed slightly more potent CYP11B2
inhibition than the gem-dimethyl parent 9, at the cost of slightly
reduced B1/B2 selectivity. The (R)-trifluoromethyl enantiomer
14 offered no advantages, being equipotent to 9 but less selective.
Similar trends were observed with (S)-trifluoromethyl enantiomer
15, which was 4-fold more potent than the corresponding gem-
dimethyl analog 11, but less B1/B2 selective.
By combining optimized indazole cores with the (S)-
trifluoromethyl tertiary alcohol-substituted pyridine, we
identified compound 34, a benchmark for our hit-to-lead efforts.
In this series, the 3-CH3-4-F, 4,7-di-F and 4-Cl-7-F derivatives
all exhibited potent CYP11B2 inhibition (Table 4, compounds 31
– 33). Unfortunately, those compounds were only modestly
selective for inhibition of CYP11B2 vs. CYP11B1. The
previously unstudied 4-CF3 indazole analog was also prepared
(compound 34), and it displayed the best combination of potent
CYP11B2 inhibition and B1/B2 selectivity observed during our
Table 3. Effect of indazole substitution on hCYP11B2 and
hCYP11B1 potency and selectivity
hit-to-lead campaign.
This result also suggested that by
increasing steric bulk at the indazole C4 position, additional
gains in B1/B2 selectivity might be realized during lead
optimization.
Table 4. Effect of indazole substitution on hCYP11B2 and
hCYP11B1 potency and selectivity
Cpd
R
CYP11B2a CYP11B1a B1/B2b
Rat Mic
Clint
c
(IC50, nM)
15
(IC50, nM)
540
8
H
36
12
25
>16
>4
15
17
9
<20
<20
83
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
7-F
0.9
11
6-F
79
2000
>8300
>8300
200
6-Cl
530
2300
13
n.d.
n.d.
30
6-CF3
5-F
Cpd
R
CYP11B2a
(IC50, nM)
CYP11B1a
(IC50, nM)
B1/B2b
5-Cl
27
470
n.d.
n.d.
n.d.
<20
n.d.
64
5-CH3
5-OCH3
5-CF3
5-CN
4-F
98
920
31
32
33
34
3-CH3-4-F
4,7-di-F
4-Cl-7-F
4-CF3
1.3
0.3
0.2
2.2
22
17
6
85
1000
1200
>8300
150
12
2
1.8
1.1
98
510
1160
8.0
5
>7
19
27
n.d.
11
20
44
4-CH3
4-CO2CH3
4,7-di-F
4-Cl-7-F
8.0
210
n.d.
n.d.
<20
n.d.
aAssay details reported in Supplementary Information.
22
n.d.
bRatio of hCYP11B1 IC50 / hCYP11B2 IC50.
0.8
8.9
0.4
7.7
aAssay details reported in Supplementary Information.
Compounds from this series exhibit high selectivity versus
related steroidal CYPs as well as major hepatic CYPs involved in
bRatio of hCYP11B1 IC50 / hCYP11B2 IC50.
drug metabolism.
As shown in Table 5, representative
compounds 13 – 15, 31, and 34 show no inhibition of CYP17 and
CYP21 (IC50s >10 M). Moderate inhibition of CYP19 was
consistently observed, but more highly optimized compounds
such as 34 typically displayed at least 2000-fold selectivity for
inhibition of CYP11B2 vs. CYP19. Indazole compounds
typically displayed little or no inhibition of hepatic CYPs 3A4
and 2D6 (IC50s generally >50 M). The one exception to that
cIntrinsic clearance in rat liver microsomes (mL/min/kg).
With data from the C3 study suggesting that prior
benzimidazole SAR would not translate directly to this series, we
undertook a fresh optimization of substitution on the indazole
core. We examined the effects of substituting indazole C4 – C7,
and found that substitution at C4 and C7 could significantly
improve potency. Thus, as shown in Table 3, simple fluorination
at C7 (compound 16) produced a >15-fold improvement in
CYP11B2 inhibition relative to the unsubstituted indazole 8. In
contrast, substitution at C6 and C5 was not well tolerated. At C6,
incorporation of fluorine, chlorine or trifluoromethyl (compounds
17 – 19) led to reductions in potency, with the magnitude of
reduction corresponding to the size of the group. At C5, small
lipophilic groups such as fluorine or chlorine were tolerated, but
offered no enhancements to potency, selectivity, or intrinsic
clearance (compounds 20 and 21). Incorporation of slightly
larger groups, be they electron-donating like methyl or methoxy
(compounds 22 and 23), or electron-withdrawing like
trend was compound 34, which inhibited CYP2D6 with an IC50
=
2.8 M, but still displayed >1000-fold selectivity for inhibition of
CYP11B2 vs. CYP2D6. Moderate inhibition of CYP2C9 was
observed across the series, but more highly optimized
compounds such as 34 displayed >4000-fold selectivity for
inhibition of CYP11B2 vs. CYP2C9. The results summarized in
Table 5 are representative of the series, and suggest reduced risk
of drug-drug interactions and other adverse events for these
compounds.

Table 5. Activity of selected compounds at steroidal and hepatic CYP targets
Cpd
CYP11B2 IC50
(nM)
CYP17 IC50
(nM)
CYP19 IC50
(nM)
CYP21 IC50
(nM)
CYP3A4 IC50
(nM)
CYP2C9 IC50
(nM)
CYP2D6 IC50
(nM)
13
14
15
31
34
14
33
>10000
>10000
>10000
>10000
>10000
6300
6200
5400
6900
4600
>10000
>10000
>10000
>10000
>10000
>50000
>50000
>50000
>50000
43000
11000
3800
7200
4700
9100
>50000
>50000
>50000
>50000
2800
77
1.3
2.2
Key compounds from this series display physical properties
that are within the ranges proposed to define lead-like property
space. Foundational texts of the physical properties literature
have advocated that clinical candidates stay within certain limits
on molecular weight, lipophilicity, number of hydrogen bond
donors and acceptors, rotatable bonds, and polar surface area.24,25
A more recent study has proposed that lead-like compounds
should ideally exhibit even lower molecular weights (MW <400)
and lipophilicities (cLog P <4) than clinical candidates to allow
room for the increases likely to occur during lead optimization.26
As shown in Table 6, representative compounds from this series,
including benchmark compound 34, meet even these more
stringent criteria for molecular weight and lipophilicity, as well
as the previously proposed criteria for hydrogen bond donors and
acceptors, rotatable bonds, and polar surface area. This series is
thus well positioned from a physical properties standpoint to
allow further development during lead optimization.
pharmacokinetic experiment, and displayed moderate oral
bioavailability and exposure, a low rate of plasma clearance, and
a half-life of nearly 8 hours.
Further improvement of
pharmacokinetic properties in this series will be pursued during
lead optimization.
Table 7. Rat pharmacokinetic profilea of compound 34
f
g
Cpd Rat Mic
Dose (iv / po)
Vd
F
AUCN
Clp
t1/2
b
Clint
(mg/kg)
(L/kg)c (%)d
(po)e
34
<20
1.0 / 2.0
6.3 28
0.85
14
7.6
a n=2 (iv), n=3 (po), Sprague-Dawley rats.
b
Intrinsic clearance in rat liver microsomes (mL/min/kg).
cVolume of distribution.
dBioavailability.
e
Area under the plasma concentration vs. time curve, normalized for dose
(M*hr*kg/mg).
Table 6. Physical properties of selected indazole compounds
f Plasma clearance (mL/min/kg).
gHalf-life (hours).
Property
MWa
Cpd 7
325
2.7
1
Cpd 13
Cpd 16
Cpd 29
Cpd 32
Cpd 34
321
3.1
1
271
2.1
1
289
2.2
1
343
2.8
1
375
3.2
1
In summary, we have reported the discovery and hit-to-lead
optimization of a novel class of indazole aldosterone synthase
inhibitors. A benchmark compound from this series displays
potent inhibition of CYP11B2, high selectivity vs. related and
hepatic CYPs, and lead-like physical and pharmacokinetic
properties. On the basis of its promising overall profile, the
indazole series was progressed into lead optimization. Further
refinements of the series have been completed, and will be
reported in due course.
cLog Pb
#HBDc
#HBAd
#Rotorse
PSA (Å2) f
3
3
3
3
3
3
3
3
2
2
3
4
52
51
53
53
53
52
References and notes
aMolecular weight.
bCalculated using Percepta ACD V.12 software.
cNumber of hydrogen bond donors.
1. Nwankwo, T.; Yoon, S.S.; Burt, V.; Gu, Q. Hypertension among
adults in the US: national health and nutrition examination survey,
2011 – 2012. NCHS Data Brief, No. 133. Hyattsville, MD:
National Center for Health Statistics, Centers for Disease Control
and Prevention, US Dept of Health and Human Services, 2013.
2. Mozaffarian, D.; Benjamin, E.; Go, A.; Arnett, D.; Blaha, M.;
Cushman, M.; de Ferranti, S.; Després, J.-P.; Fullerton, H.;
Howard, V.; Huffman, M.; Judd, S.; Kissela, B.; Lackland, D.;
Lichtman, J.; Lisabeth, L.; Liu, S.; Mackey, R.; Matchar, D.;
McGuire, D.; Mohler III, E.; Moy, C.; Muntner, P.; Mussolino,
M.; Nasir, K.; Neumar, R.; Nichol, G.; Palaniappan, L.; Pandey,
D.; Reves, M.; Rodriguez, C.; Sorlie, P. Stein, J.; Towfighi, A.;
Turan, T.; Virani, S.; Willey, J.; Woo, D.; Yeh, W.; Turner, M.
Executive summary: heart disease and stroke statistics – 2015
update. Circulation 2015, 131, e29.
dNumber of hydrogen bond acceptors.
eNumber of rotatable bonds.
f
Polar surface area calculated using TPSA method published in J. Med.
Chem., 2000, 43, 3714.
A benchmark compound from this series displayed a lead-like
pharmacokinetic profile in rat. As shown in Table 7, compound
34 was initially profiled for stability in rat liver microsomes, and
displayed a low rate of intrinsic clearance (<20 mL/min/kg),
indicating reduced propensity for metabolic oxidation via CYP-
mediated pathways. Compound 34 was then profiled in a rat
3. Calhoun, D.; Jones, D.; Textor, S.; Goff, D.; Murphey, T.; Toto,
R.; White, A.; Cushman, W.; White, W.; Sica, D.; Ferdinand, K.;
Giles, T.; Falkner, B.; Carey, R. Resistant hypertension: diagnosis,
evaluation, and treatment. Hypertension 2008, 51, 1403.

4. Tomaschitz, A.; Pilz, S.; Ritz, E.; Obermayer-Pietsch, B.; Pieber,
T. Aldosterone and arterial hypertension. Nat. Rev. Endocrinol.
2010, 6, 83.
5. Carey, R. M. Aldosterone and cardiovascular disease. Curr.
Opin. Endocrinol. Diabetes Obes. 2010, 17, 194.
6. Shavit, L.; Lifschitz, M. D.; Epstein, M. Aldosterone blockade
and the mineralocorticoid receptor in the management of chronic
kidney disease: current concepts and emerging treatment
paradigms. Kidney International 2012, 81, 955.
aldosterone synthase inhibitor for treatment of primary
hypertension. Circulation 2011, 124, 1945.
19. Azizi, M.; Amar, L.; Menard, J. Aldosterone synthase inhibition in
humans. Nephrol. Dial. Transplant. 2013, 28, 36.
20. Ali, A.; Bennett, D. J.; Cai, J.; Carswell, E.; Cooke, A.; Hoyt, S.
B.; Lo, M.; London, C.; Maclean, J.; Park, M. K.; Ratcliffe, P.;
Taylor, J. A.; Whitehead, B.; Xiong, Y. Imidazopyridyl
Compounds as Aldosterone Synthase Inhibitors. US 9173873,
11/3/2015.
7. For a recent review of aldosterone synthase inhibitors, see: Hu, Q.;
Yin, L.; Hartmann, R. W. Aldosterone synthase inhibitors as
promising treatments for mineralocorticoid dependent
21. Bennett, D. J.; Cai, J.; Carswell, E.; Cooke, A.; Hoyt, S. B.;
London, C.; Maclean, J.; Park, M. K.; Ratcliffe, P.; Xiong, Y.;
Samanta, S. K.; Kulkarni, B. A. Pyrazolopyridyl Compounds as
Aldosterone Synthase Inhibitors. US 9351973, 5/31/2016.
22. Bennett, D. J.; Cai, J.; Carswell, E.; Cooke, A.; Hoyt, S. B.;
London, C.; Maclean, J.; Ratcliffe, P.; Taylor, J. A.; Xiong, Y.;
Samanta, S. K.; Kulkarni, B. A. Triazolopyridyl Compounds as
Aldosterone Synthase Inhibitors. US 9193724, 11/24/2015.
23. Hoyt, S. B.; Taylor, J.; London, C.; Xiong, Y.; Cooke, A.
Indazole Compounds as Aldosterone Synthase Inhibitors. WO
2014099833, 6/26/2014.
24. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Experimental and computational approaches to estimate solubility
and permeability in drug discovery and development settings. Adv.
Drug Deliv. Rev. 1997, 23, 3.
25. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward,
K. W.; Kopple, K. D. Molecular properties that influence the oral
bioavailability of drug candidates. J. Med. Chem. 2002, 45, 2615.
26. Gleeson, M. P. Generation of a set of simple, interpretable
ADMET rules of thumb. J. Med. Chem. 2008, 51, 817.
cardiovascular and renal diseases. J. Med. Chem. 2014, 57, 5011.
8. Cerny, M. A. Progress toward clinically useful aldosterone
synthase inhibitors. Curr. Top. Med. Chem. 2013, 13, 1385.
9. Hoyt, S. B.; Park, M.; London, C.; Xiong, Y.; Tata, J.; Bennett, D.
J.; Cooke, J.; Cai, J.; Carswell, E.; Robinson, J.; MacLean, J.;
Brown, L.; Belshaw, S.; Clarkson, T.; Liu, K.; Liang, G.-B.;
Struthers, M.; Cully, D.; Wisniewski, T.; Ren, N.; Bopp, C.; Sok,
A.; Cai, T.-Q.; Stribling, S.; Pai, L.-Y.; Ma, X.; Metzger, J.;
Verras, A.; McMasters, D.; Chen, Q.; Tung, E.; Tang, W.;
Salituro, G.; Buist, N.; Kuethe, J.; Rivera, N.; Clemas, J.; Zhou,
G.; Gibson, J.; Maxwell, C. A.; Lassman, M.; McLaughlin, T.;
Castro-Perez, J.; Szeto, D.; Forrest, G.; Hajdu, R.; Rosenbach, M.;
Ali, A. Discovery of benzimidazole CYP11B2 inhibitors with in
Vivo activity in rhesus monkeys. ACS Med. Chem. Lett. 2015, 6,
573.
10. Hoyt, S. B.; Petrilli, W.; London, C.; Liang, G.-B.; Tata, J.; Hu,
Q.; Yin, L.; van Koppen, C. J.; Hartmann, R. W.; Struthers, M.;
Cully, D.; Wisniewski, T.; Ren, N.; Bopp, C.; Sok, A.; Cai, T.-Q.;
Stribling, S.; Pai, L.-Y.; Ma, X.; Metzger, J.; Verras, A.;
McMasters, D.; Chen, Q.; Tung, E.; Tang, W.; Salituro, G.; Buist,
N.; Clemas, J.; Zhou, G.; Gibson, J.; Maxwell, C. A.; Lassman,
M.; McLaughlin, T.; Castro-Perez, J.; Szeto, D.; Forrest, G.;
Hajdu, R.; Rosenbach, M.; Xiong, Y. Discovery of triazole
CYP11B2 inhibitors with in Vivo activity in rhesus monkeys. ACS
Med. Chem. Lett. 2015, 6, 861.
Supplementary Material
Assay protocols, replicate data and standard error for in vitro
experiments, synthesis schemes, representative procedures for the
synthesis of compounds 26, 34 and related intermediates, and X-
ray crystallographic data for an intermediate used to prepare
compounds 13 – 15 and 31 – 34.
11. Hu, Q.; Yin, L.; Ali, A.; Cooke, A. J.; Bennett, J.; Ratcliffe, P.;
Lo, M. M.-C.; Metzger, E.; Hoyt, S.; Hartmann, R. W. Novel
pyridyl substituted 4,5-dihydro-[1,2,4]-triazolo[4,3-a]quinolines as
potent and selective aldosterone synthase inhibitors with improved
in vitro metabolic stability. J. Med. Chem. 2015, 58, 2530.
12. Grombein, C. M.; Hu, Q.; Rau, S.; Zimmer, C.; Hartmann, R. W.
Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to
potent and selective inhibitors of human and rat aldosterone
synthase. Eur. J. Med. Chem. 2015, 90, 788.
13. Yin, L.; Hu, Q.; Emmerich, J.; Lo, M. M.-C.; Metzger, E.; Ali, A.;
Hartmann, R. W. J. Med. Chem. 2014, 57, 5179.
14. Meredith, E. L.; Ksander, G.; Monovich, L. G.; Papillon, J. P. N.;
Liu, Q.; Miranda, K.; Morris, P.; Rao, C.; Burgis, R.; Capparelli,
M.; Hu, Q.-Y.; Singh, A.; Rigel, D. F.; Jeng, A. Y.; Beil, M.; Fu,
F.; Hu, C.-W.; LaSala, D. Discovery and in vivo evaluation of
potent dual CYP11B2 (Aldosterone Synthase) and CYP11B1
inhibitors. ACS Med. Chem. Lett. 2013, 4, 1203.
15. Papillon, J. P. N.; Adams, C. M.; Hu, Q.-Y.; Lou, C.; Singh, A.
K.; Zhang, C.; Carvahlo, J.; Rajan, S.; Amaral, A.; Beil, M. E.; Fu,
F.; Gangl, E.; Hu, C.-W.; Jeng, A. Y.; LaSala, D.; Liang, G.;
Logman, M.; Maniara, W. M.; Rigel, D. F.; Smith, S. A.; Ksander,
G. M. Structure-activity relationships, pharmacokinetics, and in
vivo activity of CYP11B2 and CYP11B1 inhibitors. J. Med.
Chem. 2015, 58, 4749.
16. Papillon, J. P. N.; Lou, C.; Singh, A. K.; Adams, C. M.; Ksander,
G. M.; Beil, M. E.; Chen, W.; Leung-Chu, J.; Fu, F.; Gan, L.; Hu,
C.-W.; Jeng, A. Y.; LaSala, D.; Liang, G.; Rigel, D. F.; Russell, K.
S.; Vest, J. A.; Watson, C. Discovery of N-[5-(6-chloro-3-cyano-
1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide,
a cortisol-sparing CYP11B2 inhibitor that lowers aldosterone in
human subjects. J. Med. Chem. 2015, 58, 9382.
17. Martin, R. E.; Aebi, J. D.; Hornsperger, B.; Krebs, H.-J.; Kuhn,
B.; Kuglstatter, A.; Alker, A. M.; Marki, H. P.; Muller, S.; Burger,
D.; Ottaviani, G.; Riboulet, W.; Verry, P.; Tan, X.; Amrein, K.;
Mayweg, A. V. Discovery of 4-Aryl-5,6,7,8-
tetrahydroisoquinolines as potent, selective, and orally active
aldosterone synthase (CYP11B2) inhibitors: in vivo evaluation in
rodents and cynomologous monkeys. J. Med. Chem. 2015, 58,
8054.
18. Calhoun, D. C.; White, W. B.; Krum, H.; Guo, W.; Bermann, G.;
Trapani, A.; Lefkowitz, M. P.; Menard, J. Effects of a novel