Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: Carboxamide modification

Article abstract of DOI:10.1016/j.bmcl.2012.01.047

The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.

Full text of DOI:10.1016/j.bmcl.2012.01.047

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2338–2342
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationship of pyrrole based S-nitrosoglutathione
reductase inhibitors: Carboxamide modification
Xicheng Sun a, , Jian Qiu a, Sarah A. Strong a, Louis S. Green a, Jan W.F. Wasley b, Joan P. Blonder a,
⇑
Dorothy B. Colagiovanni a, Adam M. Stout a, Sarah C. Mutka a, Jane P. Richards a, Gary J. Rosenthal a
a N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, CO 80301, USA
b Simpharma LLC, 1 Stone Fence Lane, Guilford, CT 06437, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family
(ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione
(GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respira-
tory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a
potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development
for acute asthma. We describe here the synthesis and structure–activity relationships (SAR) of novel pyr-
role based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We
have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA)
induced asthma model in mice.
Received 6 October 2011
Accepted 13 January 2012
Available online 2 February 2012
Keywords:
GSNO
GSNOR
GSNOR inhibitor
Nitrosothiols
Nitric oxide
Asthma
Ó 2012 Elsevier Ltd. All rights reserved.
N6022
Nitric oxide (NO) is synthesized from
L
-arginine by nitric oxide
clinical development for the treatment of acute asthma. Following
this communication, we also disclosed the structure–activity rela-
tionship of the pyrrole based GSNOR inhibitors related to N6022
including the identification of pyrrole regioisomer 1725 and potent
GSNOR inhibitor 8f26 with reduced CYP inhibition, as shown in Fig-
ure 2. In this Letter, we discuss the synthesis and structure–activity
relationship of the pyrrole based GSNOR inhibitors mainly focusing
on the replacement and modification of the carboxamide, in an at-
tempt to further understand the structure–activity relationship
and improve enzyme inhibitory potency and ADME properties.
The general synthetic route of GSNOR inhibitors is outlined in
Scheme 1. The synthesis started from either commercially avail-
able ketones or the ketones prepared according to the procedures
described in the Supplementary data. In Scheme 1, condensation
of ketones 1 and 2-furanaldehyde provided intermediate 2 in good
yield.27 Furan ring opening of intermediates 2 by hydrogen bro-
mide in ethanol under reflux conditions provided diketones 3.28
Pyrrole formation was achieved by condensation of the diketones
3 with anilines under acidic conditions to afford compounds 4.29
The synthesis of compounds 5a–5w, where the X is bromo or meth-
oxy, was accomplished by hydrolysis of compounds 4 in aqueous
lithium hydroxide. Compounds 7a –7x were synthesized using
substituted imidazoles as starting materials to couple with inter-
synthases (NOS).1,2 S-nitrosoglutathione (GSNO), an adduct of NO
and glutathione, exists in equilibrium with other low molecular
weight and protein-bound S-nitrosothiols (SNOs). GSNO and SNOs
serve as more stable reservoirs for bioavailable NO, in comparison
to NO itself. S-nitrosoglutathione reductase (GSNOR, also known as
alcohol dehydrogenase 3) catalyzes the reduction of GSNO3,4 to the
unstable intermediate S-(N-hydroxyamino)glutathione which
spontaneously rearranges to glutathione sulfinamide or reacts
with glutathione (GSH) to form glutathione disulfide and hydroxyl-
amine.4–8 At low pH, the glutathione sulfinamide is readily hydro-
lyzed to sulfinic acid and ammonia.4 Therefore GSNOR indirectly
controls intracellular levels of SNOs and thus, NO (Fig. 1).9–16
GSNOR knockout mice have been shown to have increased lung
SNOs and were protected from airway hyperresponsiveness after
methacholine or allergen challenge, suggesting that GSNOR is a
crucial modulator of airway tone.3,17 Given such findings, GSNOR
has been recognized as a potential therapeutic target for the treat-
ment of a broad range of diseases due to the important role that
GSNO plays in the biological systems.18–23 We recently reported
the discovery of N6022,24 a potent GSNOR inhibitor that is in
Abbreviations: GSNOR, S-nitrosoglutathione reductase; GSNO, S-nitrosogluta-
thione; NO, nitric oxide; SNOs, nitrosothiols.
mediates 4 (X = Br) using
L-proline as a catalyst in the presence
⇑
Corresponding author. Tel.: +1 720 945 7706; fax: +1 303 440 8339.
E-mail address: xicheng.sun@n30pharma.com (X. Sun).
of copper iodide (I) and potassium carbonate in dimethylsulfoxide
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.047

X. Sun et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2338–2342
2339
Figure 1. Role of GSNOR enzyme.
OH
3
OH
OH
2
N
4
N
N
O
O
O
N
N
N
N
5
N
S
1
N
H2N
H2N
O
H2N
O
O
17
IC50 = 9.9 nM
8f
N6022
IC50 = 10 nM
IC50 = 6.7 nM
Figure 2. Potent GSNOR inhibitors (IC50 determined in plate format).
O
O
CO2Et
R2
Ar
X
O
CO2Et
N
Ar
X
a
Ar
X
c
b
O
Ar
X
O
1
3
4
2
R1
X = Br or OMe
d
e
R3
R3
N
N
CO2Et
R2
N
N
CO2Et
CO2H
N
Ar
Ar
N
N
e
X
R2
R2
6a - 6x
5a - 5w
7a - 7x
R1
R1
R1
Scheme 1. Synthetic route of GSNOR inhibitors. Reagents and conditions: (a) furan-2-carbaldehyde/NaOMe/MeOH, room temperature, overnight; (b) HBr/EtOH, reflux, 8 h;
(c) aniline/pTsOH/EtOH, reflux, overnight; (d) imidazole/ -proline/CuI/K2CO3/DMSO; (e) LiOH.
L
followed by hydrolysis of the ester in aqueous lithium hydrox-
ide.30,31 The synthesis of key compounds is described in the Sup-
plementary data and the other compounds were prepared in the
similar manners as detailed in our earlier publications.24–26
To examine the SAR of the amide replacement, we kept the rest of
the molecule the same, X = OMe, and R2 = H or Me (Table 1) except
compound 5w, where X is bromo. Within the des-methyl series 5a–
5i, where R2 = H, the hydroxyl analog 5a is the most potent inhibitor
followed by the amide analog 5d. Methylation of the hydroxyl ana-
log 5a (5b) resulted in a 4–5-fold loss in GSNOR inhibition activity.
Replacing the hydroxyl group with bromide 5c also diminished the
binding affinity to the enzyme. The reversed amide 5f lost 10-fold
GSNOR inhibitory activity. Spacing the amide from the phenyl ring
with either methylene 5h or NH (urea) 5i caused >10-fold loss in
the GSNOR inhibitory activity. More extensive SAR was explored
with the methyl series, where R2 = Me. Sulfonamide 5m achieved
the best activity with IC50 = 330 nM followed by the sulfonyl dia-
mide 5n. Interestingly, the hydroxyl analog 5j was not as potent
as the des-methyl comparator 5a and O-methylation also resulted
in only a minor loss in activity. Substituted amide analogs 5o and
5p were much less active than the primary amide reported earlier
(X = OMe, R1 = CONH2, R2 = Me, IC50 = 210 nM).24 However, intro-
ducing a methoxyethyl group 5q or hydroxyethyl group 5r recov-
ered some of the loss in GSNOR inhibition. Furthermore, we
prepared the heterocyclic amides 5s–5v in an attempt to pick up
more binding to the enzyme. The 4-pyridyl amide 5u demonstrated
an IC50 of 170 nM, which is the best within the series. The bromo
analog of 5u achieved double digit nanomolar IC50 (61 nM).

2340
X. Sun et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2338–2342
Table 1
Table 2
Structure–activity relationship of non-imidazole analogs
Structure–activity relationship of imidazole containing analogs
Compound
X
R1
R2
GSNOR
Compound
R1
R2
R3
Ar
GSNOR
IC50 (nM)
IC50 (nM)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
OH
OMe
Br
CONH2
COMe
NHAc
CONHMe
CH2CONH2
NHCONH2
OH
H
H
H
H
H
H
H
H
240
8f
CONH2
SO2NH2
NHSO2Me
NHSO2Me
NHSO2Me
NHCOMe
OH
NH2
CH2NH2
CO2H
NHCOMe
NHSO2Me
NHCOEt
NHCOCH2OMe
OH
OH
OH
OH
SO2NH2
NHAc
NHSO2Me
NHAc
NHSO2Me
OH
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
H
H
H
H
H
2,5-Thienyl
2,5-Thienyl
2,5-Thienyl
2,4-Thienyl
1,4-Phenyl
1,4-Phenyl
1,4-Phenyl
1,4-Phenyl
1,4-Phenyl
1,4-Phenyl
1,4-Phenyl
1,4-Phenyl
1,4-Phenyl
1,4-Phenyl
1,4-Phenyl
2,5-Thienyl
2,4-Thienyl
3,5-Thienyl
2,5-Thienyl
2,4-Thienyl
2,4-Thienyl
1,4-Phenyl
1,4-Phenyl
2,5-Thienyl
1,4-Phenyl
17 (6.7*)
22
43
1020
3250
460
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
76
960
180
450
180
1410
1590
110
56
29
88
96
54
36
96
45
23
140
360
3890
1790
32
3270
4560
Inactive
4800
1550
8840
1800
330
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OMe
H
H
H
SO2NH2
NHSO2NH2
CONHMe
CONMe2
CONH(CH2)2OMe
CONH(CH2)2OH
710
2410
1310
730
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
660
N
O
N
7s
7t
7u
7v
7w
7x
5s
4-OMe
Me
640
N
H
N
N
H
H
O
O
OH
H
39
5t
4-OMe
4-OMe
4-OMe
4-Br
Me
Me
Me
Me
440
170
3740
61
N
H
*
IC50 was determined in plate format.
N
5u
5v
5w
N
H
did not show any off-target activity in the Cerep receptor/ion chan-
nel panel, by contrast with N6022 as reported earlier.24
Compounds 7a–7c, 7k, 7r, and 7o were also screened for cyto-
toxicity towards the A549 epithelial lung cell line. The IC50 values
O
O
N
N
N
H
for all compounds tested were >150 lM.
Compounds 7o and 7x were selected for pharmacokinetic stud-
ies in mice. Oral bioavailability of these compounds was 3.9% and
6.8%, respectively, compared to 4.4% for N6022 reported previ-
ously.24 The plasma clearance (CL) after intravenous (IV) adminis-
tration was 23.9 and 37.1 ml/min/kg for 7o and 7x, respectively,
which is comparable to 37.7 ml/min/kg for N6022.24
N
H
Further SAR was explored with the imidazole series to achieve
better enzyme inhibition activity (Table 2). In comparison to 8f
published earlier,26 replacing the amide with sulfonamide 7a and
reverse sulfonamide 7b maintained the GSNOR inhibitory activity.
It is clear that exchanging the phenyl ring (7d, 7u and 7v) by thie-
nyl (7b, 7s and 7t) improved the GSNOR inhibition activity 4–10-
fold. Within the phenyl series 7f–7m, the reverse sulfonamide 7k
demonstrated the best activity, followed by the reverse amides
7j, 7l and 7m. Compounds with basic functionalities such as amine
(7g) and aminomethyl (7h) resulted in a substantial loss in GSNOR
inhibitory activity. Within the methyl imidazole series 7n–7v, 2,4-
substituted thienyl analog 7p is less active than the 2,5-disubsti-
tuted analog 7o. In the phenol series 7n–7q, 7w, and 7x, where
R1 = OH, des-methyl analog 7x seems more active than the corre-
sponding methyl analog 7f, this was not observed in the other
amide replacement compounds. Methyl imidazole 7n is also less
active than its des-methyl imidazole analog 7x.
Selected GSNOR inhibitors were screened for potential off-tar-
get activity with a panel of 55 transmembrane and soluble recep-
tors, ion channels, and monoamine transporters involved in
maintaining homeostasis of critical organ systems. Typical binding
assays were performed with a minimum of 6-control wells with/
without vehicle for soluble compounds. Inhibition of 50% or greater
was considered a positive response. Off-target effects were esti-
mated from the percent inhibition of receptor radio-ligand binding
Compound 7b was tested in a 5-day mouse toxicity study with
intravenous QD dosing at 1, 10, or 50 mg/kg. Surprisingly, despite a
better off-target activity profile of this compound compared to
N6022, the treatment of male CD-1 mice with 7b for 5 days re-
sulted in significant adverse effects. In particular, histological find-
ings demonstrated toxicity to the liver, spleen, and thymus of
treated animals. The NOAEL for 7b from the study was determined
to be 1 mg/kg/day.
The efficacy of GSNOR inhibitors was assessed in an animal
model of asthma, a disease influenced by dysregulated GSNOR
and altered function of NO, GSNO, and SNOs.32 Asthma was in-
duced by exposure of mice to OVA. 7b was given as a single
1 mg/kg IV dose 24 h prior to challenge with aerosolized metha-
choline (MCh). Other groups of mice were treated with 3 inhaled
doses of Combivent (5.2 mg/kg albuterol and 0.9 mg/kg ipratropi-
um per dose at 48, 24, and 1 h prior to MCh) or a single iv admin-
istration of PBS vehicle as study controls. Efficacy was assessed by
measuring attenuation of the MCh-induced bronchoconstriction
using whole body plethysmography (Buxco) and attenuation of
the eosinophil infiltration into the bronchoalveolar lavage fluid
(BALF). Values are means SEM of 10 mice per group. Compound
7b attenuated methacholine-induced bronchoconstriction (airway
hyper-responsiveness) and eosinophil infiltration into the lungs
following a single IV dose administered 24 h prior to the metha-
choline challenge. Significant efficacy was observed for compound
7b at dose 1 mg/kg (Figs. 3 and 4).
in the presence of 10 lM of test compound. Compound 7b and 7k

X. Sun et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2338–2342
2341
1 = baseline
2 = saline
p < 0.05 vs. vehicle control
*
3 = MCh 5 mg/mL
4 = MCh 20 mg/mL
5 = MCh 50 mg/mL
5
4
3
2
1
0
*
*
*
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
Vehicle Control
single i.v. dose
Combivent
3 inhaled doses
7b
single i.v. dose
Figure 3. Bronchodilatory action in a mouse model of OVA-induced asthma.
*p< 0.05 vs. vehiclecontrol
200,000
150,000
100,000
50,000
0
*
*
Vehicle Control
single i.v. dose
Combivent
3 inhaled doses
7b
single i.v. dose
Figure 4. Anti-inflammatory action in a mouse model of OVA-induced asthma.
In conclusion, the carboxamide substituent on the pendant
N-phenyl ring of pyrrole based GSNOR inhibitors can be replaced
by a number of functional groups such as hydroxyl, sulfonamide,
reverse amide, and reverse sulfonamide without losing significant
GSNOR inhibition activity. The thienyl analogs are generally more
potent than their phenyl counter parts. Compound 7b demon-
strated potent inhibitory activity, while having no off-target activ-
ities in the Cerep receptor/ion channel panel screening and a clean
profile in cytotoxicity assay. In vivo efficacy was achieved with 7b
in the OVA induced asthma model in mice. Compound 7b was well
tolerated when administered IV in 5-day toxicity evaluations in
mice up to 50 mg/kg. However, this compound had a less desirable
safety profile with a NOAEL of 1 mg/kg as compared to N6022 with
a NOAEL of 30 mg/kg.
Dr. Zhaojun Zhang and his colleagues at Chempartner, Shanghai for
the synthesis of some of the GSNOR inhibitors and Dr. Larry Ross at
SRI for screening GSNOR inhibitors in the enzyme assay.
Supplementary data
Supplementary data (experimental details and characterization
of selected compounds) associated with this article can be found,
in the online version, at doi:10.1016/j.bmcl.2012.01.047.
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