Discovery of S-nitrosoglutathione reductase inhibitors: Potential agents for the treatment of asthma and other inflammatory diseases

Article abstract of DOI:10.1021/ml200045s

S-Nitrosoglutathione reductase (GSNOR) regulates S-nitrosothiols (SNOs) and nitric oxide (NO) in vivo through catabolism of S-nitrosoglutathione (GSNO). GSNOR and the anti-inflammatory and smooth muscle relaxant activities of SNOs, GSNO, and NO play significant roles in pulmonary, cardiovascular, and gastrointestinal function. In GSNOR knockout mice, basal airway tone is reduced and the response to challenge with bronchoconstrictors or airway allergens is attenuated. Consequently, GSNOR has emerged as an attractive therapeutic target for several clinically important human diseases. As such, small molecule inhibitors of GSNOR were developed. These GSNOR inhibitors were potent, selective, and efficacious in animal models of inflammatory disease characterized by reduced levels of GSNO and bioavailable NO. N6022, a potent and reversible GSNOR inhibitor, reduced bronchoconstriction and pulmonary inflammation in a mouse model of asthma and demonstrated an acceptable safety profile. N6022 is currently in clinical development as a potential agent for the treatment of acute asthma.

Full text of DOI:10.1021/ml200045s

LETTER
pubs.acs.org/acsmedchemlett
Discovery of S-Nitrosoglutathione Reductase Inhibitors: Potential
Agents for the Treatment of Asthma and Other Inflammatory Diseases
Xicheng Sun,*,† Jan W. F. Wasley,‡ Jian Qiu,† Joan P. Blonder,† Adam M. Stout,† Louis S. Green,†
Sarah A. Strong,† Dorothy B. Colagiovanni,† Jane P. Richards,† Sarah C. Mutka,† Lawrence Chun,§ and
Gary J. Rosenthal†
†N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States
‡Simpharma LLC, 1 Stone Fence Lane, Guilford, Connecticut 06437, United States
§Emerald BioStructures, 7869 NE Day Road West, Bainbridge Island, Washington 98110, United States
S Supporting Information
b
ABSTRACT: S-Nitrosoglutathione reductase (GSNOR) regulates S-nitrosothiols (SNOs) and
nitric oxide (NO) in vivo through catabolism of S-nitrosoglutathione (GSNO). GSNOR and the
anti-inflammatory and smooth muscle relaxant activities of SNOs, GSNO, and NO play significant
roles in pulmonary, cardiovascular, and gastrointestinal function. In GSNOR knockout mice, basal
airway tone is reduced and the response to challenge with bronchoconstrictors or airway allergens
is attenuated. Consequently, GSNOR has emerged as an attractive therapeutic target for several
clinically important human diseases. As such, small molecule inhibitors of GSNOR were developed.
These GSNOR inhibitors were potent, selective, and efficacious in animal models of inflammatory
disease characterized by reduced levels of GSNO and bioavailable NO. N6022, a potent and
reversible GSNOR inhibitor, reduced bronchoconstriction and pulmonary inflammation in a
mouse model of asthma and demonstrated an acceptable safety profile. N6022 is currently in clinical development as a potential
agent for the treatment of acute asthma.
KEYWORDS: GSNOR, GSNO, N6022, asthma, pyrrole, nitric oxide
he reaction of glutathione with reactive nitrogen species
gives S-nitrosoglutathione (GSNO) as a major nitric oxide
intestinal epithelial cell barrier. In IBD, reduced levels of GSNO
and NO are evident and may also occur via up-regulation of
GSNOR activity.13
T
(NO) metabolite.1 S-Nitrosoglutathione reductase (GSNOR), a
member of the alcohol dehydrogenase (ADH) family,2 has been
reported to regulate intracellular S-nitrosothiols (SNOs), a
biologically important class of stable NO adducts, by reducing
GSNO.3 GSNO has been shown to elicit many biological
functions of NO and also serves as a durable depot for NO,
which has a short biological half-life.4 Increases in bioavailable
NO are associated with anti-inflammatory and smooth muscle
relaxant effects, especially in organ systems characterized by
smooth muscle and endothelial/epithelial layers such as the
respiratory, cardiovascular, and gastrointestinal systems.5ꢀ7
GSNOR dysregulation has recently been implicated in re-
spiratory diseases.8,9 Under normal conditions, NO and GSNO
can maintain lung function through their influence on bronchial
smooth muscle tone and anti-inflammatory activities.9,10 In
human asthma, there are lowered SNO concentrations in the
lungs, likely attributable to up-regulated GSNOR activity.8 Mice
with genetic deletion of GSNOR exhibit increases in lung SNOs
and are protected from airway hyperresponsivity.11 In these mice,
GSNOR has been shown to have an important influence on NO
containing species, regulation of smooth muscle tone in the
airways, and function of adrenergic receptors in lungs and
heart.5,8,12 GSNO also plays an important role in inflammatory
bowel disease (IBD). NO and GSNO maintain normal intestinal
physiology via anti-inflammatory actions and maintenance of the
Given such findings, GSNOR has emerged as a potentially
important target for the treatment of respiratory, cardiovascular,
and gastro-intestinal diseases, many of which have lowered levels
of NO as a basis to their pathophysiology.6,13ꢀ15 N30 Pharma-
ceuticals initiated a discovery effort to identify small molecule
inhibitors of GSNOR through high throughput screening of
commercially available compounds followed by structure based
lead optimization. The goal of the effort was to identify potent
GSNOR inhibitors that can be administered either intravenously
(IV) or orally (PO) to treat these diseases. In this paper, we
report potent GSNOR inhibitors with low nanomolar IC50,
which demonstrated in vivo efficacy and safety in preclinical
models and have advanced into clinical development. We also
describe the structureꢀactivity relationships of GSNOR inhibi-
tors and the crystal structure of an enzymeꢀNADþꢀinhibitor
complex, and we report some initial biological and pharmacolo-
gical properties of these inhibitors.
The majority of GSNOR inhibitors reported in this study were
synthesized according to Scheme 1 or 2. Other compounds were
Received: February 15, 2011
Accepted: March 6, 2011
Published: March 11, 2011
r
2011 American Chemical Society
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|

ACS Medicinal Chemistry Letters
LETTER
Scheme 1. Synthetic Route of GSNOR Inhibitorsa
a Conditions: (a) 2-furanaldehyde, NaOMe/MeOH. (b) conc HCl/EtOH, reflux. (c) conc HBr/EtOH, reflux. (d) aniline, TsOH/EtOH, reflux. (e)
aniline, AcOH/EtOH, reflux. (f) 1 N NaOH/EtOH, 45 °C. (g) 1 N NaOH/MeOH, 45 °C.
Scheme 2. Alternate Synthesis of GSNOR Inhibitorsa
a Conditions: (a) 2,5-dimethoxytetrahydrofuran/AcOH. (b) POCl3/DMF. (c) Ph3P = CHCO2Et, toluene, reflux. (d) potassium 3-ethoxy-3-
oxopropanoate, DMAP/piperidine/AcOH/DMF, 80 °C. (e) H2, 10% Pd/C in EtOH. (f) NBS. (g) boronic acid, Pd(PPh3)4, Na2CO3. (h) K2CO3,
H2O2/DMSO, room temperature. (i) LiOH.
synthesized using methods described in the Supporting
Information.
The GSNOR inhibitors reported here bind reversibly to the
HMGSH binding pocket.24 Although the structures of apo,
binary, and ternary complexes of GSNOR have been published,25
no crystal structure of the GSNOꢀGSNOR complex has been
reported. To guide design and optimization of GSNOR inhibi-
tors, the structures of inhibitors bound to GSNOR and NADþ
were determined by X-ray crystallography. The crystal structure
of the ternary complex of GSNOR, NADþ, and N6022 was
solved to 1.9 Å (Figure 1) (pdb code: 3QJ5). The enzymeꢀ
ligand complex crystallized as a homodimer with N6022 binding
to each GSNOR monomer through the following key interac-
tions: (1) the imidazole in the inhibitor interacts with one of the
structural zincs, which is also coordinated to histidine 66,
cysteine 44, and cysteine 173 to form the zinc coordination
tetrahedral; (2) the carboxylic acid of N6022 hydrogen bonds to
the glutamine 111 and forms a salt bridge with arginine 114 and
lysine 283 from the second monomer; (3) the N6022 carbox-
amide hydrogen bonds to glutamine 117; (4) the N6022
imidazole ring forms a πꢀπ interaction with the nicotinamide
ring of NADþ.
In Scheme 1, condensation of ketone 1 and 2-furanaldehyde
afforded intermediate 2 in high yield.16 Furan ring-opening of
intermediate 2 by HCl or HBr in alcohol under reflux conditions
provided diketone 3.17 Pyrrole formation was achieved by
condensation of diketone 3 and anilines under acidic
conditions.18 Hydrolysis of intermediate 4 by NaOH in alcohol
afforded final products 5aꢀ5j in 5ꢀ15% overall yield.
Compounds with structural variations on the phenyl ring at
the C-5 position of the pyrrole ring were synthesized according
to Scheme 2. Condensation of 4-amino-3-methylbenzamide with
2,5-dimethoxytetrahydrofuran in AcOH led to the formation of a
key intermediate pyrrole 6.19 Formylation of the pyrrole ring of 6
under the Vilsmeier conditions produced 7 in good yield. The
acrylate 8 was obtained through a Wittig reaction of 7 with
(carbethoxymethylene)triphenylphosphorane20 or reaction of
aldehyde 7 with potassium monoethyl malonate and DMAP in
DMF followed by addition of AcOH and piperidine.21 Hydro-
genation of the acrylate 8 using Pd/C afforded the propionic
ester 9, bromination of which resulted in the key building block
10.22 Derivatization of 10 with a variety of boronic acids or esters
under Suzuki conditions provided intermediate 11.23 The nitrile
11 was converted to amide 12 by K2CO3 in the presence of H2O2
in DMSO. Final hydrolysis under basic conditions afforded
13aꢀ13i, with overall yields of 5ꢀ20%.
Compound 5a (GSNOR IC50 = 570 nM), which was identi-
fied by screening a library of commercially available compounds,
was the starting point for lead optimization based on ability to
inhibit GSNOR activity in vitro (Table 1). Introduction of a
methyl group at the R3-position of the N-phenyl ring as shown in
Scheme 1 resulted in slight improvement of IC50 from 570 nM to
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LETTER
Figure 1. Dimeric structure of N6022 bound to the GSNOR enzymeꢀNADþ complex (a) and the GSNOR binding pocket of N6022 (b).
Table 1. SAR and PK Properties of GSNOR Inhibitors
compd
R1
R2
R3
GSNOR IC50 (nM)
% F
CL (mL/min/kg)
5a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
570
360
460
240
190
450
210
500
120
160
563
160
3990
3920
20
86.5
46.8
8.9
5b
H
Me
H
11.8
5c
OMe
OMe
OMe
OMe
OMe
F
5d
F
5e
Cl
14
CF3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
5f
16.2
35.4
13a
13b
13c
5g
Cl
20.7
18.0
16.3
16.0
21.4
25.5
Br
CN
OH
CF3
5h
13d
15
CONH2
N6022
16
1H-imidazol-1-yl
4.4
37.8
20.2
Cl
MeO
Cl
56
22.4
13e
17
MeO
Br
200
96
MeO
OH
21.8
2.72
22.4
33.4
5j
Cl
55
13f
18
Cl
CONH2
EtO
160
170
110
350
580
160
120
330
Cl
19
Cl
PrO
20
Cl
NMe2
NHCHO
Cl
21
Cl
13g
13h
13i
Cl
Cl
F
Cl
CF3
360 nM (5b). Substitution at the 4-position of the C5-phenyl
ring (R1) with a methoxy group also improved IC50 to 460 nM
(5c). IC50 = 210 nM was achieved by combining both function-
alities (5f). Structureꢀactivity relationships (SAR) involving
substituents at the R3 position were further explored by replacing
the methyl group with halogens (5d and 5e) or a trifluoromethyl
group (14). Slightly improved activity was observed for the
chloro analogue 5e. The R1 position was further examined by
substitution with a variety of groups. Subtle increases in potency
were obtained for the chloro 13b, bromo 13c, and hydroxyl 5h
analogues. Significant improvement was realized by substituting
the R1 position with imidazole, leading to N6022 with IC50 of 20
nM. The increased potency of N6022 can be explained by the
fact that the imidazole interacts with one of the structural Zn in
GSNOR (Figure 1). Other potential Zn binding moieties
including heterocycles were explored, but imidazole appeared
to be the best.
SAR involving substituents of the C5-phenyl ring were further
explored by substituting at both the ortho and para positions
(Table 1). In most cases, the R1 position was substituted with
chlorine for comparison and R2 was explored for its effect on IC50
and pharmacokinetic properties. When R2 was a methoxy (16),
IC50 = 56 nM was achieved. Interchanging the position of the two
groups resulted in a significant loss of potency (IC50 = 200 nM,
13e). The bromo analogue (17) of compound 16 also has a low
IC50 (96 nM). The hydroxyl analogue 5j has similar activity to its
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ACS Medicinal Chemistry Letters
LETTER
compounds were also screened for cytotoxicity toward A549
epithelial lung cells. Minimal cytotoxicity (IC50's > 100 μM) was
observed using this assay. Selected compounds were also
screened in cytochrome P450 assays. All compounds screened
in these assays exhibited minimal inhibition at 10 μM compound
concentration except N6022, which had an IC50 =0.77μMfor CYP
2C19. N6022 was negative in a hERG in vitro screen (>100 μM)
and showed no evidence of mutagenicity in a bacterial mutagen
screen.
Figure 2. Structures of tetrazole containing GSNOR inhibitors.
Selected GSNOR inhibitors were tested in 5-day toxicology
studies in mice. Compounds were administered to mice by IV or
PO routes. The selected inhibitors were well-tolerated. The no
observable adverse effect levels (NOAELs) for IV administration
of N6022, 5f, and 13c were 30, 50, and 50 mg/kg/day,
respectively. The NOAEL for PO administration of N6022 for
5 days was 100 mg/(kg day).27
Table 2. SAR of Tetrazole Containing GSNOR Inhibitors
compd
R1
R3
R4
n
GSNOR IC50 (nM)
22
23
24
25
26
27
28
29
OMe
OMe
Br
Me CONH2
Me CONH2
Me CONH2
Me CONH2
1
0
1
0
1
0
1
0
1530
2910
190
560
450
4350
300
18
Br
The efficacy of GSNOR inhibitors was assessed in animal
models of asthma and other inflammatory diseases influenced by
dysregulated GSNOR. In a mouse model of ovalbumin-induced
asthma,28 N6022 attenuated methacholine-induced broncho-
constriction (airway hyperresponsiveness) in a dose- and time-
dependent manner, with significant efficacy achieved with a
single IV dose g0.01 mg/kg and when administered from 30
min to 48 h prior to the methacholine challenge. N6022 also
significantly attenuated eosinophil infiltration into the lungs with
a single IV dose g0.0005 mg/kg.29 In a mouse model of DSS
induced IBD, N6022 demonstrated significant efficacy with
either oral or IV dosing at 1 and 10 mg/kg/day for 10 days.
The efficacy of inhibitors 5j, 5f, 13c, and 16 was assessed using
one or more of the mouse models of ovalbumin-induced asthma,
porcine pancreatic elastase (PPE)-induced COPD, DSS-induced
IBD, and a rat model of high dietary salt-induced hypertension
(DAHL/S). Significant efficacy was observed across all
models.30ꢀ32
These data suggest that GSNOR inhibitors have potential as
therapeutic agents to modulate GSNOR activity and mitigate
GSNOR-mediated pathologies in vivo. Thus, N6022 is being
advanced in preclinical studies and is currently in phase I clinical
trials for the treatment of acute asthma. Other compounds
described in this report are under evaluation for treating other
types of GSNOR-mediated diseases.
In summary, structure based lead optimization led to a number
of potent GSNOR inhibitors with favorable pharmacological
properties in multiple disease models. We have identified a
potent and reversible GSNOR inhibitor N6022, which demon-
strated excellent in vivo activity in the ovalbumin induced asthma
animal model. This compound also demonstrated an acceptable
safety profile in the nonclinical toxicology evaluations. N6022 is
currently under further development for its clinical potential to
treat acute asthma.
Br
H
H
H
H
OH
OH
OH
OH
Br
1H-imidazol-1-yl
1H-imidazol-1-yl
methoxy comparator 16. Increasing the size of the alkoxy group
at the R2 position resulted in a 2ꢀ3-fold reduction in potency
(18 and 19). Simple nitrogen containing groups did not improve
the inhibitory activity (13f, 20, and 21). Neither disubstitution
with halogens (13g and 13h) nor the CF3 (13i) improved
inhibitory activity.
Due to the potential metabolic liability of carboxylic acids, this
group was replaced with a tetrazole moiety (Figure 2, Table 2), a
commonly used bioisostere for carboxylic acid,26 connecting
through the carbon of the tetrazole ring. The data in Table 2
demonstrate that the carboxylic acid can be replaced without a
huge loss in potency, particularly when R1 was bromo (24) as
compared to its carboxylic acid counterpart 13c (IC50 = 160 nM)
or R1 was the N-imidazole group (28 and 29). The length of the
chain linking pyrrole and tetrazole (Figure 2) played a critical
role. When R1 was a relatively small group (e.g., methoxy and
bromo), better inhibition was achieved with longer alkyl chains
(22, 24, and 26). However, when R1 was a relatively larger group
such as imidazole, the shorter chain length was preferred (29),
due to size restriction in the binding pocket.
Several compounds were selected for pharmacokinetic studies
in mice. The oral bioavailability of the compounds tested ranged
from 2.72% to 86.5% (Table 1), and the plasma clearance (CL)
after IV administration ranged from 8.9 to 37.8 mL/min/kg.
Compound 5a demonstrated good oral bioavailability (86.5%),
although potency was poor. Despite the high potency of N6022,
its oral bioavailability was very low (4.4%), showing high
clearance (37.8 mL/min/kg), potentially due to the high polarity
of the imidazole. Compound 16 was the most potent non-
imidazole-containing analogue, with an oral bioavailability
of 22%.
’ ASSOCIATED CONTENT
A battery of in vitro assays was employed to assess the potential
off-target activity of the GSNOR inhibitors on 54 transmem-
brane and soluble receptors, ion channels, and monoamine
transporters. Off-target effects were estimated from the percent
inhibition of receptor radioligand binding at a 10 μM concentra-
tion of test compound. Limited off-target activity was observed
toward the δ2 opiate receptor for N6022 (66% inhibition); no
other potential off-target activity was detected. Selected
S
Supporting Information. Experimental details and char-
b
acterization of selected compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: xicheng.sun@n30pharma.com.
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LETTER
’ ACKNOWLEDGMENT
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The authors are grateful to Dr. J. Singh and his team at deCode
chemistry for the synthetic chemistry support. We also thank Dr.
Zhaojun Zhang and his colleagues at Chempartner for the
synthesis of some of the inhibitors and Larry Ross at SRI for
screening GSNOR inhibitors in the enzyme assay.
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GSNOR, S-nitrosoglutathione reductase; GSNO, S-nitrosoglu-
tathione; NO, nitric oxide; SNO, nitrosothiol
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