Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: Pyrrole regioisomers and propionic acid replacement

Article abstract of DOI:10.1016/j.bmcl.2011.04.086

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, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach.

Full text of DOI:10.1016/j.bmcl.2011.04.086

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3671–3675
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationships of pyrrole based S-nitrosoglutathione
reductase inhibitors: Pyrrole regioisomers and propionic acid replacement
Xicheng Sun a, , Jian Qiu a, Sarah A. Strong a, Louis S. Green a, Jan W. F. Wasley b, Dorothy B. Colagiovanni a,
⇑
Sarah C. Mutka a, Joan P. Blonder a, Adam M. Stout a, Jane P. Richards a, Lawrence Chun c, 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
c Emerald BioStructures, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
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, cardiovas-
cular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selec-
tive, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development.
We describe here the synthesis and structure–activity relationships (SAR) of novel pyrrole based ana-
logues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally
potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based
approach.
Received 23 March 2011
Revised 14 April 2011
Accepted 19 April 2011
Available online 24 April 2011
Keywords:
GSNOR
GSNOR inhibitor
GSNO
Nitric oxide
Pyrrole
Ó 2011 Elsevier Ltd. All rights reserved.
N6022
The enzyme S-nitrosglutathione reductase (GSNOR) belongs to
the alcohol dehydrogenase (ADH) family.1 GSNOR is a Class III
ADH encoded by the ADH 5 gene in humans and GSNOR is also
referred to as formaldehyde dehydrogenase (FDH) which oxidizes
ease (COPD),16 altered vascular tone, thrombosis, and altered plate-
let function,17,18 pulmonary hypertension,19 cerebral ischemia,20
inflammatory bowel disease (IBD)13 and compromised host
defense.21
S-hydroxymethyl-glutathione,
a
spontaneous adduct formed
Given this critical position in the NO-SNO continuum, GSNO
provides a therapeutically promising target to consider when NO
modulation is pharmacologically warranted. Inhibition of the
GSNOR enzyme becomes a potential therapeutic approach for the
treatment of many diseases in which lowered levels of NO contrib-
ute to their pathophysiology.22–24
As one of a series of communications on GSNOR inhibitors after
the identification of N6022,24 we describe here the synthesis and
structure–activity relationship of pyrrole based GSNOR inhibitors.
We focused on the compounds with the pyrrole ring scaffold ori-
ented in different position (regioisomers) and the propionic acid
modifications. This work was guided by ligand bound crystal struc-
tures in an attempt to identify GSNOR inhibitors with improved
pharmacological properties and to provide further insights to the
enzyme–inhibitor interactions.
Compounds 9a–9y in Tables 1–3 were synthesized according to
Scheme 1. The synthetic route outlined in Scheme 1 allowed rapid
SAR development to explore the possibility of replacing the propi-
onic acid through parallel synthesis in the later stage of the
synthetic sequence. Commercially available 4-bromo-2-methyl-
benzoic acid 1 was activated by thionyl chloride and treated with
methanol to obtain methyl ester 2 in high yield. Compound 2
between formaldehyde and glutathione for formaldehyde
metabolism.2
GSNOR was recently shown to be the major enzyme that
catabolizes S-nitrosoglutathione (GSNO)3,4 by converting GSNO to
S-hydroxylamino-glutathione (GS-NHOH).5 Importantly, GSNOR
shows specificity toward GSNO rather than other substrates.3,4
GSNO is one of the major, biologically stable nitric oxide (NO) ad-
ducts of cysteine containing peptides and proteins.6,7 GSNO is an
efficient agent of protein trans-nitrosylation and thus plays a criti-
cal role in maintaining the balance of S-nitrosothiols (SNOs). Since
SNOs serve as a stable pool of NO, they provide a source of bioactive
NO and thus are likely to be critically important in health and dis-
ease given the centrality of NO in cellular homeostasis.8 Dysregula-
tion of GSNO is implicated in many disorders such as respiratory,
cardiovascular, and gastrointestinal diseases,9–13 more specifically
in asthma,12,14 cystic fibrosis,15 chronic obstructive pulmonary dis-
Abbreviations: GSNOR, S -nitrosoglutathione reductase; GSNO, S-nitrosogluta-
thione; NO, nitric oxide; SNOs, nitrosothiols.
⇑
Corresponding author. Tel.: +1 720 945 7706; fax: +1 303 440 8339.
E-mail address: xicheng.sun@n30pharma.com (X. Sun).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.086

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X. Sun et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3671–3675
Table 1
Table 3
SAR of pyrrole regioisomers
SAR of propionic acid replacement
Compd
ID
R4
R5
H
GSNOR
IC50
Compd
R3
GSNOR IC50
0.85
(l
M)a
(nM)a
9l
5fc
OMe
Cl
180
R5
CO2
OH
H
16c
OMe 54
H
CO2H
CO2H
CO2H
6022c 1H-
10 (20)b
N
9m
9n
9o
0.28
1.57
3.47
Imidazol-
1-yl
R4
CO2
H
H
F
CO2
H2N
R5
O
Cl
16a
16b
17
OMe
Cl
1H-
Imidazol-
1-yl
H
160
OMe 49
H
N
9.9
CO2
H
R4
N
9p
9q
9r
9s
8.53
29.56
>100
0.46
CO
2
H
N
H2N
O
N
660
R5
9a
18
OMe
H
H
CO
2
H
(520)b
35
1H-
Imidazol-
1-yl
R4
CO
F
H
2
—
—
—
—
OH
F
H2N
O
a
b
c
IC50 determined in plate method.
IC50 determined in cuvette method.
See Ref. 24.
9t
0.45
OH
F
CO
H
2
9u
9v
9w
9x
9y
0.41
0.19
Table 2
OH
NO2
OH
SAR of GSNOR inhibitors containing substituted propionic acid
0
Compd
R1
R2, R2
GSNOR IC50 (l
M)a
9b
9c
9d
9e
9f
9g
9h
9i
Me
Pr
cPr
iPr
Ph
H
H
H
H
H
H, H
H, H
H, H
H, H
14.06
63.67
>100.0
97.15
8.84
1.97
8.09
1.51
23.53
>100.0
21.61
3.02
N
N
OH
OH
H, H
Me, H
CH2-CH2
F, F
OH, H
NH2, H
9j
9k
28.35
SO NH
2
2
a
IC50 determined in cuvette method.
a
IC50 was determined in cuvette method.
was converted to cyano intermediate 3 using copper cyanide in
DMF. Hydrolysis of the ester 3 under basic conditions followed
by chlorination with thionyl chloride afforded compound 4. Acyla-
tion of ethyl 2-(4-methoxyphenyl)acetate by intermediate 4 in the
presence of LiHMDS in THF provided compound 5.25 Intermediate
5 was decarboxylated in an aqueous DMSO solution at high tem-
perature to obtain compound 6.26 Alkylation of intermediate 6
using allyl bromide27 followed by ozonolysis gave the key interme-
diate 7.28,29 Pyrrole ring formation was achieved by heating a vari-
ety of amines in the presence of pyridinium p-toluenesulfonate in
ethanol to obtain compounds 8a–8y.30 Hydrolysis of nitrile inter-
mediates 8a–8y using NaOH in the presence of H2O2 in DMSO
yielded final products 9a–9y.
cyclization of compound 11 with anilines.31 Basic hydrolysis of
intermediate 12 in the presence of H2O2 in DMSO yielded amide
13. Reduction of the ester 13 using DIBAL-H, followed by oxidation
by MnO2 in DCM furnished aldehyde 14 in good yield. Wittig reac-
tion of compound 14 with (carbethoxymethylene)triphenylphos-
phorane in toluene yielded acrylate 15.32 Compounds 16a and
16b can be prepared by hydrogenation of intermediate 15 followed
by basic hydrolysis.
Compounds 17 and 18 in Table 1 were prepared by following
the procedures described in the Supplementary Data.
In reviewing the crystal structure of N6022 (pdb code: 3QJ5)
bound to GSNOR and NAD+,24 it can be seen that a number of ami-
no acid side chains (Leu109, Thr309, Ala317, and Val308) form a
hydrophobic cleft around the pyrrole ring’s 3 and 4-positions
(Figs. 1 and 2). These residues also form van der Waals interactions
with the hydrocarbon chains of the substrates 12-hydroxy-dodeca-
noic acid (12-HDDA) and dodecanoate.33 We hypothesized that
Compounds 16a and 16b can be synthesized according to
Scheme 2. Acylation of ethyl acetate by intermediate 4 under basic
conditions in THF provided intermediate 10. Alkylation of com-
pound 10 with allyl bromide followed by ozonolysis afforded inter-
mediate 11. The pyrrole intermediates 12 were prepared through

X. Sun et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3671–3675
3673
O
O
O
O
NC
O
OEt
g
d,e
f
a,b
c
OMe
Cl
OH
OMe
NC
Br
Br
NC
O
OMe
1
2
4
5
3
R2'
R2'
R2
R1
R2
OH
OH
N
N
O
O
O
O
R1
MeO
NC
h, i
j
CN
k
H2N
O
8a-8k
9a-9k
O
NC
O
OMe
O
R3
N
N
R3
7
6
O
O
CN
H2N
O
8l-8y
9l-9y
Scheme 1. Synthetic route of GSNOR inhibitors. Reagents and conditions: (a) SOCl2; (b) MeOH; (c) CuCN/DMF; (d) NaOH; (e) SOCl2; (f) ethyl 2-(4-methoxyphenyl)acetate/
LiHMDS/THF; (g) H2O/DMSO, 150 °C; (h) allyl bromide/LiHMDS/THF; (i) O3/DCM/SMe2; (j) amine/PPTS/EtOH, 50–60 °C; (k) H2O2/NaOH/DMSO, rt.
R5
O
O
O
O
N
NC
NC
a
e
R4
OEt
b, c
d
Cl
OEt
OEt
NC
O
O
O
4
10
11
12
CN
R5
R5
R5
R5
O
O
COOEt
N
CO2H
N
N
N
f, g
h
i, j
R4
R4
R4
R4
OEt
O
NH2
O
NH2
O
NH2
O
NH2
13
15
14
16a and 16b
Scheme 2. Synthesis of GSNOR inhibitor. Reagents and conditions: (a) EtOAc, LDA/THF; (b) allyl bromide, NaH/THF; (c) O3/Me2S; (d) aniline, PPTS/EtOH; (e) NaOH, H2O2/
DMSO; (f) DIBAL-H; (g) MnO2/DCM; (h) Ph3P@CHCO2Et/toluene, reflux; (i) H2, Raney Ni; (j) LiOH, MeOH/H2O.
moving the nitrogen position from the 1,5-diaryl substituted orien-
tation (N6022) in Figure 2 to the 1,2-diaryl substituted orientation
(17) or to the 2,3-diaryl substituted orientation (18) should main-
tain the GSNOR inhibitory activity. The assay results indicated that
the initial hypothesis was valid, particularly with the nitrogen
moving to the 1,2-diaryl orientation (Table 1, 16a, 16b, and 17).
The compounds are equally potent to the corresponding compara-
tors previously reported (5f, 16, and N6022).24 The compounds
made from the other regioisomer lost 3- to 4-fold potency (9a
and 18) as compared to compounds 5f and N6022.
The low oral bioavailability of pyrrole based GSNOR inhibitors
reported earlier24 may be partially attributed to the high flexibility
of the propionic acid moiety. We conjectured that substitution of
the propionic acid should have considerable effects on conforma-
tion and rigidity as well as impacts on potency against GSNOR
and pharmacokinetic properties such as oral bioavailability. We
decided to further constrain the propionic acid chain by substitu-
tion with a variety of groups. Due to the synthetic difficulty of syn-
thesizing analogues of the propionic acid attached to the 2-position
of the pyrrole (Table 1) and the fact that the pyrrole regioisomers
maintained most of the potency against GSNOR, the structure–
activity relationship of the propionic acid analogues was explored
using the 2,3-diaryl substituted pyrrole regioisomer as a scaffold as
shown in Scheme 1 (compounds 9a–9y). The regioisomer (9a) of
compound 5f published earlier24 demonstrated an IC50 = 520 nM
(Table 1). Substitution at the R1 position with alkyl and phenyl
groups resulted in a tremendous loss of enzyme inhibition activity
(Table 2).
Substitution at the R2 position did not improve the inhibitory
activity either (9g–9K), particularly with polar functional groups
such as hydroxyl (9j) and amino (9k). The difluoro analogue (9i)
lost the least enzyme inhibitory activity with IC50 = 1.51 lM.
As we learned from the SAR of another series of GSNOR inhibi-
tors34 and from the crystal structures of the GSNOR enzyme bound

3674
X. Sun et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3671–3675
Figure 1. Crystal structure of N6022 bound to GSNOR–NAD+ complex: potential hydrophobic interactions of the pyrrole ring of N6022 with Leu109, Thr309, Ala317, and
Val308 with the protein backbone (a) and without the protein backbone (b); orange colored ball represents Zn.
Hydrophobic pocket
Val308
Thr309
Leu109
OH
Ala317
5
4
3
4
3
5
3
2
4
OH
OH
1
5
1
N
N
N
1
2
O
2
O
O
N
N
N
N
N
N
H2N
O
H2N
O
H2N
O
17
N6022
1,5-diaryl substituted
18
2,3-diaryl substituted
1,2-diaryl substituted
Figure 2. Structures of pyrrole regioisomers of N6022.
to inhibitors,24 replacing the propionic acid moiety with a more
structurally constrained functional group, such as benzoic acid,
may still maintain or improve the inhibitory activity of the inhibi-
tors. This was indeed the case. A replacement of propionic acid
with benzoic acid maintained the enzyme inhibition activity (9l)
kg for 5f. We did not test other compounds in the pharmacokinetic
study due to the lack of GSNOR potency of these compounds.
Potential off-target activity of the GSNOR inhibitors was as-
sessed on a panel of 54 transmembrane and soluble receptors,
ion channels, and monoamine transporters. Off-target effects were
estimated from the percent inhibition of receptor radio-ligand
at IC50 = 0.85 lM (Table 3). Introducing halogens at the ortho-posi-
tion of the carboxylic acid of compound 9l did not improve the po-
binding in the presence of 10 lM test compound. Typical binding
tency against GSNOR (9n and 9o). However, the ortho-hydroxyl
assays were performed with a minimum of six control wells
with/without vehicle for soluble compounds. Inhibition of 50% or
greater was considered a positive response. Limited off-target
activity was observed towards the d2 opiate receptor for com-
pound 17 and 18, similar to N6022 as reported earlier24; no other
potential off-target activity was detected. Although compound 9m
and 9v demonstrated better potency against GSNOR as compared
to their propionic acid counterpart (9a), more off-target activities
were observed with these two compounds, hitting five or more tar-
gets in the panel as compared to no off-target activity with 9a.
Compounds 9a and 17 were also screened for cytotoxicity towards
the A549 epithelial lung cell line. Minimal cytotoxicity (IC50s
analogue (9m) slightly improved the IC50 to 0.28
hexyl analogue (9r) of compound 9l did not show any inhibition
activity at 100 M. Replacement of the phenyl ring by pyridyl re-
lM. The cyclo-
l
sulted in a drastic loss in potency against GSNOR (9p and 9q).
The carboxylic acid was also replaced with substituted phenol
functionalities to mimic its acidity, which is critical for the binding
of inhibitor to enzyme. All compounds (9s–9v) demonstrated sub-
micromolar IC50 and the 2-nitro analogue (9v) achieved the best
IC50 in the series (Table 3). Similar to the carboxylic acid series
(9p and 9q), when the phenyl ring was replaced with pyridine
(9w and 9x), the enzyme inhibitory activity diminished. The
replacement of the carboxylic acid with a sulfonamide (9y) re-
sulted in a tremendous loss of inhibitory activity.
>250 lM) was observed using this assay.
In summary, based on the crystal structure, GSNOR inhibitors
with a pyrrole ring scaffold oriented in different positions (regioi-
somers) were synthesized and the enzyme inhibition activity of
these compounds was found to be either equal or slightly less than
the comparator compounds. These findings validated the initial
Compound 9a was tested for pharmacokinetic studies in mice.
Oral bioavailability of this compound was 12.2% as compared to
16.2% for 5f reported earlier.24 The plasma clearance (CL) after IV
administration was 52.3 ml/min/kg as compared to 35.4 ml/min/

X. Sun et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3671–3675
3675
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Supplementary data
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