Discovery of benzimidazole oxazolidinediones as novel and selective nonsteroidal mineralocorticoid receptor antagonists

Article abstract of DOI:10.1021/acsmedchemlett.5b00010

Elaboration of the oxazolidinedione series led to replacement of the exocyclic amides with substituted benzimidazoles. The structure-activity relationship (SAR) exploration resulted in the discovery of potent and selective nonsteroidal mineralocorticoid receptor (MR) antagonists with significantly improved microsomal stability and pharmacokinetic (PK) profile relative to the HTS hit 1a. One compound 2p possessed comparable efficacy as spironolactone (SPL) at 100 mg/kg (p.o.) in the rat natriuresis model. As such, this series was validated as a lead series for further optimization.

Full text of DOI:10.1021/acsmedchemlett.5b00010

Letter
pubs.acs.org/acsmedchemlett
Discovery of Benzimidazole Oxazolidinediones as Novel and
Selective Nonsteroidal Mineralocorticoid Receptor Antagonists
Christine Yang,* Jaume Balsells, Hong D. Chu, Jason M. Cox, Alejandro Crespo, Xiuying Ma,
Lisa Contino, Patricia Brown, Sheng Gao, Beata Zamlynny, Judyann Wiltsie, Joseph Clemas,
JeanMarie Lisnock, Jack Gibson, Gaochao Zhou, Margarita Garcia-Calvo, Thomas J. Bateman,
Vincent Tong, Ling Xu, Martin Crook, Peter Sinclair, and Hong C. Shen*
Merck Research Laboratories, Merck & Co., Kenilworth, New Jersey 07033, United States
S
* Supporting Information
ABSTRACT: Elaboration of the oxazolidinedione series led to replacement of the exocyclic amides with substituted
benzimidazoles. The structure−activity relationship (SAR) exploration resulted in the discovery of potent and selective
nonsteroidal mineralocorticoid receptor (MR) antagonists with significantly improved microsomal stability and pharmacokinetic
(PK) profile relative to the HTS hit 1a. One compound 2p possessed comparable efficacy as spironolactone (SPL) at 100 mg/kg
(p.o.) in the rat natriuresis model. As such, this series was validated as a lead series for further optimization.
KEYWORDS: mineralocorticoid receptor, antagonist, amide replacement, oxazolidinedione, natriuresis effect
he mineralocorticoid receptor (MR) is a nuclear hormone
receptor located in the sodium ion-transporting epithelia
(e.g., kidney, colon) and nonepithelia tissues including heart,
blood vessels, brain, and salivary and sweat glands.1 The major
endogenous ligand for MR is aldosterone (A in Figure 1), which
hypertensive patients treated with diuretics.3 This result is often
in part due to both an abnormal activation of MR by elevated
levels of aldosterone and salt imbalance, which may cause
hypertension and other detrimental effects to the vasculature.
Hence, direct MR antagonism has been utilized as an alternative
or adjunct therapy for cardiovascular diseases. For example,
spironolactone4 (SPL) and eplerenone5 (EPL) are two marketed
MR antagonists (Figure 1) used successfully to treat hyper-
tension and heart failure. However, use of SPL is limited due to
sexual adverse effects including gynecomastia and menstrual
irregularities, which mainly result from the off-target activity
related to the androgen receptor (AR). While EPL is significantly
more selective than SPL, resulting in a lower incidence of
gynecomastia, it is less efficacious than SPL, as reflected by EPL’s
inferior potency and pharmacokinetic (PK) profile.6
In light of the current limitations of the marketed MR
antagonists, a potent and selective small molecule MR antagonist
may provide clinicians with an additional valuable tool for
treating hypertension and CHF. Toward this end, several classes
of nonsteroidal MR antagonists have emerged over the past few
years.7−15 Herein, we report our preliminary efforts on the
discovery of benzimidazole oxazolidinediones as a novel class of
potent MR antagonists.
T
Figure 1. Structures of MR antagonists SPL, SPL, and EPL.
plays an essential role in salt and water homeostasis by retaining
sodium and water. Aldosterone binding in MR triggers a cascade
of events including modulation of gene expression and protein
synthesis, which then promote renal sodium reabsorption and
potassium excretion in the distal nephron. Patients with primary
hyperaldosteronism frequently suffer from hypertension, which
may be driven by high MR activity leading to sodium
reabsorption and fluid retention.2
The inhibition of the renin−angiotensin−aldosterone system
by angiotensin-converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers (ARBs) has been established
as a successful approach in treating hypertension and congestive
heart failure (CHF).3 Unfortunately, ACE inhibitors or ARBs fail
to reach blood pressure lowering goals in a significant number of
Received: January 13, 2015
Accepted: March 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00010
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Starting from the high-throughput screening hit 1a (Figure 2),
a preliminary study provided a series of nonsteroidal, potent, and
Tables 1 and 2 summarize the efforts in optimizing the R1 moiety
of the scaffold, namely, the 5- and 4-positions of the
benzimidazole, respectively.
Analogues containing small halides (2a, 2c, 3b), trifluor-
omethyl (2d, 3c), alkoxide (2e), nitrile (2i), amide (2h), and
sulfonamide (2f, 3e) provided modest MR activity with IC50
values ranging from 100 to 500 nM in the functional assay.
Substituting benzimidazole with heteroaryls or heterocycles at
the 4-position led to several compounds (2k, 2l, 2n, 2o, 2p, 2q,
2s, 2t, 2u) with improved IC50 values below 100 nM. In contrast,
the analogues bearing 4-subsituted heteroaryls (3f−3k) were, in
general, less active than the 5-substituted counterparts (2j−2o,
2q−2u).
Most compounds depicted in Table 1 had acceptable human
microsomal stability (>50% of parent remaining after 30 min of
incubation). The rat microsomal stability varied significantly
depending on the substituents of the benzimidazole. Two types
of modifications were adopted to successfully improve the rat
liver microsomal stability of compounds. The first was to
introduce sulfonamide functionality (2f), and the second was to
place a heteroaryl group (2j, 2k, 2m, 2o, 2p) at the 5-position of
the benzimidazole moiety.
Figure 2. Evolutions leading to benzimidazole oxazolidinedione
analogues.
Substitution at the 4-position of benzimidazole (Table 2) also
had a profound impact on the rat liver microsomal stability. The
trifluoromethyl analogue 3c had the highest rat microsomal
stability followed by amide 3d and sulfonamide 3e.
selective oxazolidinedione MR antagonists.16 However, these
compounds, in general, had poor liver microsomal stability; they
were almost completely metabolized in 30 min upon incubation
in the presence of human or rat liver microsomes. The in vitro
metabolite identification study revealed that the primary
metabolic pathways of these compounds originated from the
hydrolysis of the amide, dealkylation of the benzylamine moiety,
and extensive oxidation of the three aromatic groups. In light of
these findings, aniline-derived amide 1b was prepared in order to
minimize the N-dealkylation of the benzylamine. In addition,
fluorine and chlorine atoms were introduced to two of the three
aryl groups in order to reduce their propensity toward oxidative
metabolism. While these additions did not improve rat liver
microsomal stability (MS, 0%), measured by the remaining
parent molecule at 30 min postincubation, they did increase the
human liver microsomal stability (44%). Furthermore, the MR
antagonist potency of 1b was significantly increased relative to
1a. It was further envisaged that the issue of amide hydrolysis
could be solved by replacing the amide group with a heterocyclic
bioisostere, such as monocyclic heteroaryls including oxadiazole,
triazole, or imidazole, as described previously.17 Alternatively, we
envisage that a bicyclic heteroaryl such as benzimidazole might
provide distinct structure−activity relationships (SARs) and
different properties. Gratifyingly, analogue 2a, the first
benzimidazole analogue prepared in this series, not only
displayed similar MR potency as 1b but also demonstrated
improved rat liver microsomal stability. Thus, a new
benzimidazole-based oxazolidinedione class emerged.
Related to MR are other nuclear hormone receptors, such as
androgen receptor (AR), glucocorticoid receptor (GR), estrogen
receptor (ER), and progesterone receptor (PR). It is critical to
develop MR antagonists with excellent selectivity to avoid off-
target mediated adverse effects. As such, cell-based reporter gene
assays were performed with a panel of nuclear hormone
receptors including human AR, GR, ERα, ERβ, and PRβ
(Table 3). As described in Table 3, SPL (B) had modest
selectivity for MR over AR (∼60-fold) and some residual activity
against GR and PRβ. In contrast, EPL (C) displayed remarkable
selectivity against other nuclear hormone receptors examined.
While SPL, EPL, and benzimidazole oxazolidinediones were
typically completely inactive in the agonist mode of the cell-
based counterscreening assays, the selectivity in the antagonist
mode continued to be a challenge. Most oxazolidinediones
appeared to have some GR, AR, ERα, ERβ, and PRβ antagonist
activity. Several compounds, such as 2o, 2p, and 2q, displayed
over 40-fold selectivity profile across the board, which represents
a significant improvement over the previously described
compounds (>5-fold).17 Compared to SPL, which had a 60-
fold selectivity against AR, compounds 2o and 2q had a
selectivity of 90- and 110-fold, respectively.
The PK profiles of a subset of compounds in rats are shown in
Table 4. A range of oral bioavailability (6−54%) was observed for
these compounds, of which 2d, 2o, 2p, and 3c had modest to
good bioavailability. It is worth noting that several compounds
(2a, 2d, 2q, and 3c) displayed high plasma protein binding
(>99%) in whole plasma, and thus, free fraction was typically
measured in the presence of 10% plasma and presumed to be
correlated to the free fraction in total plasma. By introducing
polar substituents to benzimidazole such as a sulfonamide (2f,
3e), heteroaryl (2m), or heterocycle (2p), higher plasma free
fraction was observed, and generally rat liver microsomal stability
was improved as well (Tables 1 and 2).
Compounds generated during the hit-to-lead process were
screened for in vitro activity against human MR in a cell-based
functional assay (hMR-NH-Pro),18 which is a commercially
available PathHunter protein−protein interaction assay that
measures the ability of compounds to antagonize full-length
human MR binding to a coactivator peptide. In this assay, the
average IC50 values for SPL and EPL were 11 and 240 nM,
respectively. In addition, most compounds were also charac-
terized in human and rat liver microsome stability assays.
The exploration of the SAR with respect to the R2 and R3
regions of scaffold D (Figure 2) indicates that phenyl and 4-
fluorophenyl, respectively, afforded the best activity against MR.
Potent MR antagonists with reasonable rat PK were further
evaluated in an acute rat pharmacodynamic model, which
measured the amount of urinary sodium excretion (natriuresis)
B
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Table 1. In Vitro SAR of 5-Substituted Benzimidazole
Analogues
Table 2. In Vitro SAR of 4-Substituted Benzimidazole
Analogues
a
a
a
Values are the average of two experiments, each in 10-point titrations.
Percent remaining at 0.5 h and 1 μM incubation in human (h) and
b
rat (r) liver microsomes (LM).
Table 3. Nuclear Hormone Receptor Selectivity of
Representative Analogues (NH_PRO Antagonist Mode
Assay)
MR IC50 GR IC50 AR IC50 ERα IC50 ERβ IC50 PRβ IC50
compd
(μM)
(μM)
(μM)
(μM)
(μM)
(μM)
B
0.011
0.24
4.1
18
0.67
>20
3.1
3.0
13
>20
>20
3.3
3.0
17
>20
>20
2.4
2.7
12
4.0
>20
2.4
3.2
4.9
2.9
2.8
1.9
2.9
8.2
C
2a
2d
2f
0.16
3.8
3.4
>20
3.0
2.9
4.9
3.1
17
0.12
0.22
2m
2o
2p
2q
3e
0.12
3.1
3.4
7.7
3.7
11
6.3
4.9
6.1
7.9
>20
2.6
3.0
5.3
2.7
7.3
0.039
0.040
0.034
0.21
over 6 h after a single oral dose, using SPL as a positive control. It
should be noted that rat and human MRs have 90% identity, and
the two proteins share the exactly same DNA and ligand binding
domains. Therefore, compounds are presumed to have similar
human and rat MR activities.19 Of several compounds being
tested (2a, 2f, 2j, 2p, and 2q) in the natriuresis rat model, 2a, 2f,
and 2q exhibited a modest but statistically significant PD effect (p
< 0.05). Furthermore, compound 2p had the most pronounced
a
Values are the average of two experiments, each in 10-point titrations.
Percent remaining at 0.5 h and 1 μM incubation in human (h) and
b
rat (r) liver microsomes (LM).
C
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Letter
a
Table 4. Rat PK Profiles and Plasma Protein Binding Data in Human and Rat Plasma (10%)
compd
F%
Clp (mL/min/kg)
Vdss (L/kg)
T1/2 (h)
AUCNpo (μM·h·kg/mg)
free fraction in 10% plasma (%, human, rat)
2a
2d
2f
15
36
6
47
33
32
19
20
67
80
23
55
4.6
3.4
1.8
1.6
1.9
2.3
5.0
3.4
3.2
1.5
1.7
1.6
1.8
1.2
0.69
0.94
2.4
1.2
0.11
0.2, 1
0.33
0.2, 0.7
3.4, 6.4
4, 1.7
0.067
0.49
2m
2o
2p
2q
3c
3e
27
54
44
11
44
15
0.79
-
0.07
9.3, 6.5
0.2, 0.8
0.2, 0.5
5.8, 6.4
0.046
0.067
0.085
a
Values are an average of two wistar han rats for IV dose and three rats for p.o. dose. Formulation: The IV doses were formulated at 1 mg/kg in
DMSO/PEG200/water (10:60:30), and the oral doses were formulated at 2 mg/kg in imwitor/tween (1:1) and given by oral gavage. F%, oral
bioavailability; Clp, plasma clearance; Vdss, volume of distribution; Cmax, observed maximal plasma concentration following oral dosing; T1/2, terminal
half-life; AUCNpo; normalized area under the curve for oral dosing.
a
dose-dependent natriuretic effect as shown in Figure 3, and the
effect at 100 mg/kg was comparable to SPL at 30 or 100 mg/kg.
Scheme 1
Figure 3. Dose-dependent natriuretic effect of SPL and 2p in WKY rats.
Vehicle: inwitor/tween, 2 mL/kg. Animals fed with low salt diet; jugular
vein bleedings were performed 6 h postdose for drug exposure (mpk,
mg/kg; *, p < 0.05 vs vehicle; #, p < 0.05 vs 2p 10 mg/kg).
Interestingly, previous amide replacement by monocyclic
heteroaryls17 exhibited much weaker efficacy at the same doses
in the same model (data not shown). Taking in vivo efficacy and
selectivity into consideration, there are unique advantages of
using substituted benzimidazoles as replacement of amide.
A representative synthesis of oxazolidinedione analogues is
illustrated in Scheme 1. The α-hydroxylation of malonate 4,
applying vigorous air bubbling over 3 days, afforded the
hydroxylated intermediate 5, which then underwent a mono-
hydrolysis to yield monocarboxylic acid 6. Subsequent chiral
supercritical fluid chromatography (SFC) separation provided
the chiral acid 7, which was then coupled with 1-chloro-3,4-
benzenediamine to generate amide intermediate 8, followed by
heating in acetic acid to yield the benzimidazole intermediate 9.
Finally, the reaction of the benzimidazole 9 with isocyanate 10 in
the presence of NaOH provided compound 2a. The cross-
coupling reaction of 11, the 5-Br analogue of 2a, with various
boronic acids/esters generated the corresponding heteroaryl-
substituted analogues. For example, the Suzuki coupling of
compound 11 and pyrimidine boronic acid 12 afforded 2u in
good yield.
a
Reagents and conditions: (a) CsF, DMF, 40 °C to rt, 3 d, 71%; (b)
KOH, EtOH, 46%, rt, overnight; (c) chiral SFC (OJ-H, 4.6 × 100 mm,
5% MeOH/0.1% TFA/CO2, 2.5 mL/min, 100 bar); (d) HATU,
iPr2NEt, 1-chloro-3,4-benzenediamine, DMF, overnight; (e) AcOH,
75 °C, 2 h, 58% over 2 steps; (f) NaOH, THF, 70 °C, 25 min, 77%;
(g) Pd(OAc)2, dppf, K3PO4, EtOH, 120 °C, microwave, 5 min, 76%.
polar substituent led to several MR antagonists with acceptable
rat PK, potency against MR, and selectivity against other nuclear
hormone receptors. Ultimately, analogue 2p demonstrated
similar natriuretic effect in rats as SPL at 100 mg/kg. As such,
the benzimidazole oxazolidinedione class became a validated lead
series for further optimization, which will be reported in due
course.
In summary, oxazolidinediones derived from the HTS hit 1a
represent a novel class of MR antagonists. SAR studies were
directed to enhance potency and human and rat liver microsomal
stability, as well as rat PK in order to elicit PD effects in rats.
Improvements in liver microsomal stability and PK were realized
by replacing the central amide functionality with benzimidazole.
The endeavor of optimizing the benzimidazole series by adding a
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, NMR, LC/MS data, and chiral
separation. This material is available free of charge via the
Internet at http://pubs.acs.org.
D
DOI: 10.1021/acsmedchemlett.5b00010
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ACS Medicinal Chemistry Letters
Letter
derivatives as novel, potent, and selective nonsteroidal mineralocorti-
coid receptor antagonists. J. Med. Chem. 2011, 54, 8616−8631.
(14) Piotrowski, D. W. Mineroalocorticoid receptor antagonists for the
treatment of hypertension and diabetic nephropathy. J. Med. Chem.
2012, 55, 7957−7966.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: hongshen@stanfordalumni.org.
*E-mail: christine_yang@merck.com.
(15) Casimiro-Garcia, A.; Piotrowski, D. W.; Ambler, C.; Arhancet, G.
B.; Banker, M. E.; Banks, T.; Boustany, C. M.; Cai, C.; Chen, X.; Eudy,
R.; Hepworth, D.; Hulford, C. A.; Jennings, S. M.; Loria, P. M.; Meyers,
M. J.; Petersen, D. N.; Raheja, N. K.; Sammons, M.; She, L.; Song, K.;
Vrieze, D.; Wei, L. Identification of (R)-6-(1-(4-cyano-3methylphenyl)-
5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl-2−15methoxynicotinic acid,
a highly potent and selective nonsteroidal mineralocorticoid receptor
antagonist. J. Med. Chem. 2014, 57, 4273−4288.
(16) Yang, C.; Shen, H. C.; Wu, Z.; Chu, H. D.; Cox, J. M.; Balsells, J.;
Crespo, A.; Brown, P.; Zamlynny, B.; Wiltsie, J.; Clemas, J.; Gibson, J.;
Contino, L.; Lisnock, J.; Zhou, G.; Garcia-Calvo, M.; Bateman, T.; Xu,
L.; Tong, X.; Crook, M.; Roy, S.; Tata, J. R.; Sinclair, P. Discovery of
novel oxazolidinedione derivatives as potent and selective mineralo-
corticoid receptor antagonists. Bioorg. Med. Chem. Lett. 2013, 23, 4388−
4392.
(17) Cox, J. M.; Chu, H. D.; Yang, C.; Shen, H. C.; Wu, Z.; Balsells, J.;
Crespo, A.; Brown, P.; Zamlynny, B.; Wiltsie, J.; Clemas, J.; Gibson, J.;
Contino, L.; Lisnock, J.; Zhou, G.; Garcia-Calvo, M.; Bateman, T.; Xu,
L.; Tong, X.; Crook, M.; Sinclair, P. Mineralocorticoid receptor
antagonists: identification of heterocyclic amide replacements in the
oxazolidinedione series. Bioorg. Med. Chem. Lett. 2014, 24, 1681−1684.
(18) Nuclear Hormone Receptors. http://www.discoverx.com/nhrs/
prod-nhrs.php.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) Chai, W.; Danser, A. H. Why are mineralocorticoid receptor
antagonists cardioprotective? Naunyn-Schmiedeberg’s Arch. Pharmacol.
2006, 374, 153−162 and references therein.
(2) Funder, J. W. Glucocorticoid and mineralocorticoid receptors:
Biology and clinical relevance. Annu. Rev. Med. 1997, 48, 231−240 and
references therein..
(3) McKelvie, R. S.; Yusuf, S.; Pericak, D.; Avezum, A.; Burns, R. J.;
Probstfield, J.; Tsuyuki, R. T.; White, M.; Rouleau, J.; Latini, R.;
Maggioni, A.; Young, J.; Pogue, J. Comparison of candesartan, enalapril,
and their combination in congestive heart failure, randomized evaluation
of strategies for left ventricular dysfunction (RESOLVD) pilot study, the
RESOLVD pilot study investigators. Circulation 1999, 100, 1056−1064.
(4) Ouzan, J.; Perault, C.; Lincoff, A. M.; Carre, E.; Mertes, M. The role
of spironolactone in the treatment of patients with refractory
hypertension. Am. J. Hypertens. 2002, 15, 333−339.
(5) Krum, H.; Nolly, H.; Workman, D.; He, W.; Roniker, B.; Krause, S.;
Fakouhi, K. Efficacy of eplerenone added to renin-angiotensin blockade
in hypertensive patients. Hypertension 2002, 40, 117−123.
(19) UniProt. http://www.uniprot.org.
́
(6) Parthasarathy, H. K.; Menard, J.; White, W. B.; Young, W. F., Jr;
Williams, G. H.; Williams, B.; Ruilope, L. M.; McInnes, G. T.; Connell, J.
M.; MacDonald, T. M. A double-blind, randomized study comparing the
antihypertensive effect of eplerenone and spironolactone in patients
with hypertension and evidence of primary aldosteronism. J. Hypertens.
2011, 29, 980−990.
(7) Neel, D. A.; Brown, M. L.; Lander, P. A.; Grese, T. A.; Defauw, J.
M.; Doti, R. A.; Fileds, T.; Kelley, S. A.; Smith, S.; Zimmerman, K. M.;
Steinberg, M. I.; Jadhav, P. K. 3,3-Bisaryloxindoles as mineralocorticoid
receptor antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 2553−2557.
(8) Meyers, M. J.; Hu, X. Non-steroidal mineralocorticoid receptor
antagonists. Expert Opin. Ther. Pat. 2007, 17, 17−23.
(9) Bell, M. D.; Gernert, D. L.; Grese, T. A.; Belvo, M. D.; Borromeo, P.
S.; Kelley, S. A.; Kennedy, J. H.; Kolis, S. P.; Lander, P. A.; Richey, R.;
Sharp, V. S.; Stephenson, G. A.; Williams, J. D.; Yu, H.; Zimmerman, K.
M.; Steinberg, M. I.; Jadhav, P. K. (S)-N-{3-[1-Cyclopropyl-1-(2,4-
difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: A potent,
nonsteroidal, functional antagonist of the mineralocorticoid receptor. J.
Med. Chem. 2007, 50, 6443−6445.
(10) Arhancet, G. B.; Woodard, S. S.; Dietz, J. D.; Garland, D. J.;
Wagner, G. M.; Iyanar, K.; Collins, J. T.; Blinn, J. R.; Numann, R. E.; Hu,
X.; Huang, H.-C. Stereochemical requirements for the mineralocorti-
coid receptor antagonist activity of dihydropyridines. J. Med. Chem.
2010, 53, 4300−4304.
(11) Arhancet, G. B.; Woodard, S. S.; Iyanar, K.; Case, B. L.; Woerndle,
R.; Dietz, J. D.; Garland, D. J.; Collins, J. T.; Payne, M. A.; Blinn, J. R.;
Pomposiello, S. I.; Hu, X.; Heron, M. I.; Huang, H. C.; Lee, L. F.
Discovery of novel cyanodihydropyridines as potent mineralocorticoid
receptor antagonists. J. Med. Chem. 2010, 53, 5970−5978.
(12) Meyers, M. J.; Arhancet, G. B.; Hockerman, S. L.; Chen, X.; Long,
S. A.; Mahoney, M. W.; Rico, J. R.; Garland, D. J.; Blinn, J. R.; Collins, J.
T.; Yang, S.; Huang, H.-C.; McGee, K. F.; Wendling, J. M.; Dietz, J. D.;
Payne, M. A.; Homer, B. L.; Heron, M. I.; Reitz, D. B.; Hu, X. Discovery
of (3S, 3aR)-2-(3-chloro-4-cynaophenyl)-3-cyclopentyl-3, 3a, 4, 5-
tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF3883845), an
orally efficacious mineralocorticoid receptor (MR) antagonist for
hypertension and nephropathy. J. Med. Chem. 2010, 53, 5979−6002.
(13) Hasui, T.; Matsunaga, N.; Ora, T.; Ohyabu, N.; Nishigaki, N.;
Imura, Y.; Igata, Y.; Matsui, H.; Motoyaji, T.; Tanaka, T.; Habuka, N.;
Sogabe, S.; Ono, M.; Siedem, C. S.; Tang, T. P.; Gauthier, C.; De Meese,
L. A.; Boyd, S. A.; Fukumoto, S. Identification of benzoxazin-3-one
E
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