Synthesis and evaluation of tetrahydropyrazolopyridine inhibitors of anion exchange protein SLC26A4 (pendrin)

Article abstract of DOI:10.1016/j.bmcl.2019.07.003

Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treatment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine condensation was been developed. Structure-activity relationships at the tetrahydropyridyl nitrogen were investigated using a focused library, establishing the privileged nature of N-phenyl ureas and improving inhibitor potency by greater than 2-fold.

Full text of DOI:10.1016/j.bmcl.2019.07.003

Accepted Manuscript
Synthesis and Evaluation of Tetrahydropyrazolopyridine Inhibitors of Anion
Exchange Protein SLC26A4 (Pendrin)
Jie S. Zhu, Julia Y. Lu, Joseph-Anthony Tan, Amber A. Rivera, Puay-Wah
Phuan, Marina E. Shatskikh, Jung-Ho Son, Peter M. Haggie, Alan S. Verkman,
Mark J. Kurth
PII:
S0960-894X(19)30448-2
https://doi.org/10.1016/j.bmcl.2019.07.003
BMCL 26544
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
1 May 2019
29 June 2019
1 July 2019
Please cite this article as: Zhu, J.S., Lu, J.Y., Tan, J-A., Rivera, A.A., Phuan, P-W., Shatskikh, M.E., Son, J-H.,
Haggie, P.M., Verkman, A.S., Kurth, M.J., Synthesis and Evaluation of Tetrahydropyrazolopyridine Inhibitors of
Anion Exchange Protein SLC26A4 (Pendrin), Bioorganic & Medicinal Chemistry Letters (2019), doi: https://
doi.org/10.1016/j.bmcl.2019.07.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.
Me
F
N
H
N
N
N
F
O
O
Cl
Regioselective pyrazole synthesis
Pendrin IC50 = 3.1 M

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis and Evaluation of Tetrahydropyrazolopyridine Inhibitors of Anion
Exchange Protein SLC26A4 (Pendrin)
a
a
b
b
b
Jie S. Zhu , Julia Y. Lu , Joseph-Anthony Tan , Amber A. Rivera , Puay-Wah Phuan , Marina E.
a
a
b
b
a
Shatskikh , Jung-Ho Son , Peter M. Haggie , Alan S. Verkman , Mark J. Kurth
a
Department of Chemistry, University of California, Davis, California 95616, United States
Departments of Medicine & Physiology, University of California, San Francisco, California 94143, United States
b
ARTICLE INFO
ABSTRACT
Keywords:
pendrin
SLC26A4
anion transporter
pyrazole
regioselectivity
Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways
in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the
regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treat-
ment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-
pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine conden-
sation was been developed. Structure-activity relationships at the tetrahydropyridyl nitrogen
were investigated using a focused library, establishing the privileged nature of N-phenyl ureas
and improving inhibitor potency by greater than 2-fold.
—
——

Corresponding author. e-mail: mjkurth@ucdavis.edu (M. J. Kurth)

Pendrin (PDS) is a 780 amino acid sodium-independent
chloride/anion antiporter containing twelve putative
– one of the most privileged functional groups in drug
2
5
discovery – was prevalent in PDS and SLC26A3 inhibitors
2
1, 26
transmembrane spanning domains and cytoplasmic amino and
discovered by high-throughput screening (Fig 1B).
We
1
carboxy-termini. The PDS gene (SLC26A4) was identified by
reasoned that developing a versatile route to TPP compounds
would be valuable because chemical synthesis affords us the
opportunity to generate a focused library at the tetrahydropyridyl
nitrogen. Herein, we report the development of a completely
regioselective route to the TPP core and structural analogs to
further investigate structure–activity relationships for this class of
compounds.
positional cloning in subjects with the autosomal recessive
disorder Pendred syndrome, which is characterized by hearing
2
impairment and thyroid goiter. Functional studies show that PDS
–
mediates electroneutral exchange of Cl with various anions
–
–
–
–
including I , HCO
3
, OH , and SCN at the apical membrane of
epithelial cells in the inner ear, thyroid, kidney, airways, and
1
, 3-8
adrenal gland.
PDS upregulation is observed in the airways of
Work began by resynthesizing the original active compound
humans with rhinovirus infection, asthma, cystic fibrosis and
chronic rhinosinusitis, in rodent models of inflammatory
pulmonary disease including asthma, infection, and toxin
exposure, and in airway epithelial cultures after exposure to
inflammatory cytokines.9-19 PDS knockout reduces pathology in
various mouse models of inflammatory lung diseases.15, 20 The
mechanism of PDS involvement in pulmonary inflammation is
thought to involve regulation of airway surface liquid (ASL)
volume. Small molecule PDS inhibitors increase airway hydra-
tion in cytokine-stimulated human airway epithelial cultures.21
Together, these studies support the therapeutic utility of PDS
inhibitors for lung diseases including asthma and cystic
(
1). However, controlling the position of the N-methyl group was
a major challenge due to regioselectivity issues associated with
2
7
pyrazole synthesis. Indeed, it is known that pyrazoles do not
undergo selective N-alkylations and the reaction of N-substituted
hydrazine with unsymmetrical 1,3-diketones is also not
regioselective. Despite these challenges, the Knorr pyrazole
synthesis remains one of the most robust and reliable methods for
accessing these nitrogen heterocycles. In order to address this
regioselectivity problem, we took advantage of the benzylic
2
CH –O moiety in the lead compound (Scheme 1). This moiety
allowed us to attempt the Knorr pyrazole synthesis using an 1,3-
diketone with an electron withdrawing group attached (10).
Theoretically, the presence of the electron withdrawing group
should activate the α-carbonyl, allowing selective pyrazole
formation to occur.
2
7
2
2, 23
fibrosis.
Prior screening of 36,000 synthetic, drug-like small molecules
identified several chemical classes of PDS inhibitors containing a
tetrahydro-1H-pyrazolo[4,3-c]pyridine (TPP) core, with the most
potent compound having an IC50 of ~7 μM for both human and
murine PDS (Fig 1A).21, 24 Analysis of commercially available
TPP pendrin inhibitor analogs revealed minimal opportunities for
mod-
Scheme 2. Regioselective synthesis of the lead compound.
O
N
N
O
A) TPP pendrin inhibitor from high-throughput screening
Low substitution
a
b
OEt
c
decagram scale
Me
O
tolerance
SAR opportunities
N
N
N
N
Boc
Boc
Boc
H
N
N
N
F
11
12
13
O
O
Cl
1
B) Sulfur-containing targets from high-throughput screening
Me
F
Me
N
N
N
N
F
O
Br
g
f
H
O
gram scale
Me
N
Me
S
N
N
N
O
H
N
Boc
Boc
N
N
S
N
S
Me
15
14
N
H
O
Br
2
3
h
Me
F
O
S
N
N
O
F
NH
S
O
Me
F
O
S
N
N
O
Cl
O
i
O
NH
N
S
S
O
O
NH
Cl
N
H
N
S
16
1
Me
Me
4
5
Fig 1. Previously identified inhibitors of SLC26A4 and SLC264A3
ification of the pyrazole nitrogen or ether oxygen.21 While
substitutions at the tetrahydropyridyl nitrogen were relatively
underexplored in the commercial library, the sulfonamide moiety

Scheme 2. Regioselective synthesis of the lead compound. Reagents and conditions: (a) pyrrolidine, toluene, Dean-Stark,
reflux; (b) ethyl chlorooxoacetate, Et N, DCM, rt; (c) DCM, 1 M HCl, rt, 85% over 3 steps; (d) methylhydrazine, EtOH,
reflux, 52%; (e) LiBH , Et O, reflux, 66%; (f) PPh , NBS, DCM, rt, 84%; (g) 3-fluorophenol, Cs CO , DMF, 90 °C, 90%;
h) TFA, DCM, rt; (i) 4-chlorophenyl isocyanate, DCM (anh), rt, 77% over 2 steps.
3
4
2
3
2
3
(
Me
F
N
N
O
Me
Me
reaction time to three days did not give a higher yield of 7.
Routine purification of pyrazole 7 was straightforward because
the undesired regioisomer was not formed/detected throughout
the course of the reaction. This reaction was repeated on large
scale and the structure of 7 was confirmed using X-ray
crystallography (Scheme 2). Subsequent reduction of 7 using
N
N
N
N
OH
OEt
N
O
O
NH
Cl
N
N
1
Boc
6
Boc
7
4
LiBH gave the corresponding alcohol in 66% yield. Alcohol 6
high
regioselectivity
required
was converted to bromide 14 in 84% yield using an Appel
28
reaction. It should be noted that NBS could be substituted
2
completely by Br with little impact on the yield of the Appel
reaction. Reaction of 3-fluorophenol with 14 under basic
conditions gave the targeted ether in 90% yield. The Boc group
of 15 was more resilient than expected, as deprotection using
varying concentrations of HCl ranging from 1 to 6 M was
ineffective in both methanol and dioxane. Boc deprotection was
finally accomplished using TFA in DCM, followed by a basic
work up to give amine 16. Reaction of 16 with 4-chlorophenyl
isocyanate gave the lead compound 1 in 77% yield over the last
two steps. The synthesized 1 had a similar potency compared to
commercial 1 (Figure 2).
O
O
O
O
OEt
OEt
Cl
O
O
N
N
Boc
8
9
Boc 10
Scheme 1. Retrosynthetic analysis.
The synthesis of 1 (Scheme 2) began with a Stork enamine
synthesis between N-Boc piperidin-4-one and ethyl 2-chloro-2-
oxoacetate. Hydrolysis of 13 using a biphasic system of DCM
and aqueous HCl gave the ester-containing 1,3-diketone 10 in
5% yield over 3 steps at 25 g scale. Next, methylhydrazine was
refluxed with 10 to deliver pyrazole 7 as the only regioisomer in
2% yield. Note, the reaction can also be stopped after just one
day of reflux, but the yield of 7 decreases to 33%. Increasing the
As previously described, a functional cell-based assay of PDS-
–
–
mediated Cl /I exchange was used to measure the PDS inhibition
2
1, 24
activity of TPP analogs.
In brief, Fischer rat thyroid cells
8
stably expressing murine PDS and a halide-sensitive fluorescent
protein (EYFP-H148Q/I152L/F46L) were used. PDS activity was
determined from the kinetics of fluorescence decrease in
5
–
response to addition of an I -containing solution to cells, with
–
–
inhibitors reducing the rate of Cl /I exchange and hence the rate
of reduction in fluorescence.
A small set of ether analogs were synthesized to address the
effect of fluorine substitution (Table 1). These minor
modifications improved PDS inhibition activity compared to
compound 1. Analogs 17 and 18 inhibited PDS with IC50 of 4.6
and 3.3 μM, while 3,5-difluoro-substituted 19 resulted in an IC50
of 3.1 μM. Ester analog 20 and carboxylic acid analog 21 both
had minimal PDS inhibition activity.
Table 1. Synthesized TPP with varying substitution at benzylic
position and activity against PDS.
O
Me
N
N
Cl
NH
N
R1
Comp.
R1
PDS IC50
F
F
O
O
6
.6 µM
.6 µM
1
4
17
19
18
F
F
F
O
O
3
.1 µM
.3 µM
F
3
F

attempts to incorporate sulfur into the molecule via thioureas
were not successful at increasing PDS inhibition activity. This
series of analogs gave insights into the privileged nature of the N-
phenyl urea, as both alkyl and acylated ureas performed poorly.
In summary, we developed a completely regioselective route
to tetrahydropyrazolopyridines and synthesized a focused library
of analogs with substitution at the tetrahydropyridyl nitrogen.
This chemistry allowed us to further investigate the structure-
activity relationship of this class of PDS inhibitors. Introduction
of an additional fluorine atom significantly improved the IC50
from ~7 μM to ~3 μM. Although the sulfur atom was well-
represented in other classes of SLC26 inhibitors, sulfur analogs
such as thioureas, sulfonamides, and sulfuric diamide were not
useful for PDS inhibition activity. Indeed, throughout the course
of these studies. N-phenyl ureas were found to be highly
privileged.
Fig 2. Concentration-dependence for inhibition of pendrin anion
exchange by synthesized and commercial 1, and by 19.
Moving forward, the effect of substitution at the
tetrahydropyridine nitrogen was investigated (see Fig 1A).
Although previous high-throughput screening revealed that
sulfonamides were common structural features among hit
compounds, minimal inhibition activity was observed when
sulfonamides were introduced into the TPP scaffold even when
the 4-chlorophenyl moiety was preserved (Table 2). Similarly,
Acknowledgments
This work was supported by the National Institutes of Health
(
DK072517 and DK067003). J.S.Z. is supported by a fellowship
Table 2. TPP with different substitution patterns at
tetrahydropyridyl nitrogen and activity against PDS.
from the UC Davis Tara K. Telford CF Fund, UC Davis
Dissertation Year Fellowship, and R. Bryan Miller Graduate
Fellowship. M.E.S. is supported by the UC Davis Provost’s
Undergraduate Fellowship.
isocyanate
isothiocyanate
or sulfonyl chloride
Me
F
Me
F
N
N
N
N
O
O
Supplementary Material
F
F
N
N
H
R1
Supplementary data containing detailed synthesis procedures,
1H, 13C, and crystallography information (X-ray coordinates have
been deposited with the Cambridge Crystallographic Data Centre
under CCDC 1913463).
Comp.
R1
PDS IC50
3.3 µM
O
22
23
24
25
26
27
28
29
HN
O
Br
References and Notes
1
2
3
4
.
.
.
.
Royaux, I. E.; Suzuki, K.; Mori, A.; Katoh, R.; Everett, L. A.;
Kohn, L. D.; Green, E. D., Pendrin, the protein encoded by the
Pendred syndrome gene (PDS), is an apical porter of iodide in
the thyroid and is regulated by thyroglobulin in FRTL-5 cells.
Endocrinology 2000, 141, 839-845.
Everett, L. A.; Glaser, B.; Beck, J. C.; Idol, J. R.; Buchs, A.;
Heyman, M. a.; Adawi, F.; Hazani, E.; Nassir, E.; Baxevanis, A.
D.; Sheffield, V. C.; Green, E. D., Pendred syndrome is caused
by mutations in a putative sulphate transporter gene (PDS). Nat.
Genet. 1997, 17, 411-422.
Pedemonte, N.; Caci, E.; Sondo, E.; Caputo, A.; Rhoden, K.;
Pfeffer, U.; Di Candia, M.; Bandettini, R.; Ravazzolo, R.;
Zegarra-Moran, O., Thiocyanate transport in resting and IL-4-
stimulated human bronchial epithelial cells: role of pendrin and
anion channels. J. Immunol. 2007, 178, 5144-5153.
>10 µM
>10 µM
>10 µM
>10 µM
>10 µM
>10 µM
>10 µM
HN
O
O
HN
Ph
O
HN
S
HN
S
Cl
HN
S
N(CH3)2
Royaux, I. E.; Wall, S. M.; Karniski, L. P.; Everett, L. A.;
Suzuki, K.; Knepper, M. A.; Green, E. D., Pendrin, encoded by
HN
O
S
Me
O
O

the Pendred syndrome gene, resides in the apical region of renal
intercalated cells and mediates bicarbonate secretion. Proc.
Natl. Acad. Sci. USA 2001, 98, 4221-4226.
Scott, D. A.; Karniski, L. P., Human pendrin expressed in
Xenopus laevis oocytes mediates chloride/formate exchange.
Am. J. Physiol. Cell Physiol. 2000, 278, C207-C211.
Scott, D. A.; Wang, R.; Kreman, T. M.; Sheffield, V. C.;
Karniski, L. P., The Pendred syndrome gene encodes a chloride-
iodide transport protein. Nat. Genet. 1999, 21, 440.
Shcheynikov, N.; Yang, D.; Wang, Y.; Zeng, W.; Karniski, L.
P.; So, I.; Wall, S. M.; Muallem, S., The Slc26a4 transporter
functions as an electroneutral Cl−/I−/HCO3− exchanger: role of
Slc26a4 and Slc26a6 in I− and HCO3− secretion and in
regulation of CFTR in the parotid duct. J. Physiol. 2008, 586,
18. Seshadri, S.; Lu, X.; Purkey, M. R.; Homma, T.; Choi, A. W.;
Carter, R.; Suh, L.; Norton, J.; Harris, K. E.; Conley, D. B.;
Kato, A.; Avila, P. C.; Czarnocka, B.; Kopp, P. A.; Peters, A.
T.; Grammer, L. C.; Chandra, R. K.; Tan, B. K.; Liu, Z.; Kern,
R. C.; Schleimer, R. P., Increased expression of the epithelial
anion transporter pendrin/SLC26A4 in nasal polyps of patients
with chronic rhinosinusitis. J. Allergy Clin. Immunol. 2015,
136, 1548-1558.e7.
19. Yick, C. Y.; Zwinderman, A. H.; Kunst, P. W.; Grunberg, K.;
Mauad, T.; Dijkhuis, A.; Bel, E. H.; Baas, F.; Lutter, R.; Sterk,
P. J., Transcriptome sequencing (RNA-Seq) of human
endobronchial biopsies: asthma versus controls. Eur. Respir. J.
2013, 42, 662-70.
5
6
7
.
.
.
20. Scanlon, K. M.; Gau, Y.; Zhu, J.; Skerry, C.; Wall, S. M.;
Soleimani, M.; Carbonetti, N. H., Epithelial anion transporter
pendrin contributes to inflammatory lung pathology in mouse
models of Bordetella pertussis infection. Infect. Immun. 2014,
82, 4212-21.
3
813-3824.
8
9
.
.
Soleimani, M.; Greeley, T.; Petrovic, S.; Wang, Z.; Amlal, H.;
Kopp, P.; Burnham, C. E., Pendrin: an apical Cl−/OH−/HCO3
−
exchanger in the kidney cortex. Am. J. Physiol. Renal. Physiol.
2
001, 280, F356-F364.
21. Haggie, P. M.; Phuan, P. W.; Tan, J. A.; Zlock, L.; Finkbeiner,
W. E.; Verkman, A. S., Inhibitors of pendrin anion exchange
identified in a small molecule screen increase airway surface
liquid volume in cystic fibrosis. FASEB J. 2016, 30, 2187-97.
22. Li, H.; Salomon, J. J.; Sheppard, D. N.; Mall, M. A.; Galietta, L.
J., Bypassing CFTR dysfunction in cystic fibrosis with
alternative pathways for anion transport. Curr. Opin.
Pharmacol. 2017, 34, 91-97.
23. Sala-Rabanal, M.; Yurtsever, Z.; Berry, K. N.; Brett, T. J.,
Novel Roles for Chloride Channels, Exchangers, and Regulators
in Chronic Inflammatory Airway Diseases. Mediators Inflamm.
2015, 2015, 13.
24. Cil, O.; Haggie, P. M.; Phuan, P.-w.; Tan, J.-A.; Verkman, A.
S., Small-Molecule Inhibitors of Pendrin Potentiate the Diuretic
Action of Furosemide. J. Am. Soc. Nephrol. 2016, 27, 3706-
3714.
25. Scott, K. A.; Njardarson, J. T., Analysis of US FDA-Approved
Drugs Containing Sulfur Atoms. Top. Curr. Chem. 2018, 376,
5.
Adams, K. M.; Abraham, V.; Spielman, D.; Kolls, J. K.;
Rubenstein, R. C.; Conner, G. E.; Cohen, N. A.; Kreindler, J.
L., IL-17A Induces Pendrin Expression and Chloride-
Bicarbonate Exchange in Human Bronchial Epithelial Cells.
PLoS One 2014, 9, e103263.
1
1
0. Clarke, L. A.; Sousa, L.; Barreto, C.; Amaral, M. D., Changes
in transcriptome of native nasal epithelium expressing F508del-
CFTR and intersecting data from comparable studies. Respir.
Res. 2013, 14, 38.
1. Fujita, K.; Morimoto, Y.; Endoh, S.; Uchida, K.; Fukui, H.;
Ogami, A.; Tanaka, I.; Horie, M.; Yoshida, Y.; Iwahashi, H.;
Nakanishi, J., Identification of potential biomarkers from gene
expression profiles in rat lungs intratracheally instilled with
C(60) fullerenes. Toxicology 2010, 274, 34-41.
2. Ishida, A.; Ohta, N.; Suzuki, Y.; Kakehata, S.; Okubo, K.;
Ikeda, H.; Shiraishi, H.; Izuhara, K., Expression of pendrin and
periostin in allergic rhinitis and chronic rhinosinusitis. Allergol
Int 2012, 61, 589-95.
3. Kuperman, D. A.; Lewis, C. C.; Woodruff, P. G.; Rodriguez, M.
W.; Yang, Y. H.; Dolganov, G. M.; Fahy, J. V.; Erle, D. J.,
Dissecting asthma using focused transgenic modeling and
functional genomics. J. Allergy Clin. Immunol. 2005, 116, 305-
1
1
26. Haggie, P. M.; Cil, O.; Lee, S.; Tan, J.-A.; Rivera, A. A.;
Phuan, P.-W.; Verkman, A. S., SLC26A3 inhibitor identified in
small molecule screen blocks colonic fluid absorption and
reduces constipation. JCI Insight 2018, 3.
1
1.
27. Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y. N.;
Al-Aizari, F. A.; Ansar, M., Synthesis and Pharmacological
Activities of Pyrazole Derivatives: A Review. Molecules 2018,
23.
28. Appel, R., Tertiary Phosphane/Tetrachloromethane, a Versatile
Reagent for Chlorination, Dehydration, and P––N Linkage.
Angew. Chem. Int. Ed. Engl. 1975, 14, 801-811.
1
1
4. Lewis, C. C.; Yang, J. Y. H.; Huang, X.; Banerjee, S. K.;
Blackburn, M. R.; Baluk, P.; McDonald, D. M.; Blackwell, T.
S.; Nagabhushanam, V.; Peters, W.; Voehringer, D.; Erle, D. J.,
Disease-specific gene expression profiling in multiple models of
lung disease. Am. J. Respir. Crit. Care Med. 2008, 177, 376-
3
87.
5. Nakagami, Y.; Favoreto, S., Jr.; Zhen, G.; Park, S.-W.;
Nguyenvu, L. T.; Kuperman, D. A.; Dolganov, G. M.; Huang,
X.; Boushey, H. A.; Avila, P. C.; Erle, D. J., The epithelial
anion transporter pendrin is induced by allergy and rhinovirus
infection, regulates airway surface liquid, and increases airway
reactivity and inflammation in an asthma model. Am. J.
Immunol. 2008, 181, 2203-2210.
1
6. Nakao, I.; Kanaji, S.; Ohta, S.; Matsushita, H.; Arima, K.;
Yuyama, N.; Yamaya, M.; Nakayama, K.; Kubo, H.; Watanabe,
M.; Sagara, H.; Sugiyama, K.; Tanaka, H.; Toda, S.; Hayashi,
H.; Inoue, H.; Hoshino, T.; Shiraki, A.; Inoue, M.; Suzuki, K.;
Aizawa, H.; Okinami, S.; Nagai, H.; Hasegawa, M.; Fukuda, T.;
Green, E. D.; Izuhara, K., Identification of pendrin as a
common mediator for mucus production in bronchial asthma
and chronic obstructive pulmonary disease. J. Immunol. 2008,
1
80, 6262-9.
1
7. Oh, J.-H.; Yang, M.-J.; Heo, J.-D.; Yang, Y.-S.; Park, H.-J.;
Park, S.-M.; Kwon, M.-S.; Song, C.-W.; Yoon, S.; Yu, I. J.,
Inflammatory response in rat lungs with recurrent exposure to
welding fumes: a transcriptomic approach. Toxicol. Ind. Health
2
011, 28, 203-215.