Identification of an adamantyl azaquinolone JNK selective inhibitor

Article abstract of DOI:10.1021/ml300175c

3-[4-((1S,2S,3R,5S,7S)-5-Hydroxyadamantan-2-ylcarbamoyl)benzyl] -4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (4) was identified as a novel, druglike and selective quinolone pan JNK inhibitor. In this communication, some of the structure-activity relationship of the azaquinolone analogues leading to 4 is discussed. The focus is on how changes at the amide functionality affected the biochemical potency, cellular potency, metabolic properties, and solubility of this class of JNK inhibitors. Optimization of these properties led to the identification of the adamantyl analogue, 4. 4 achieved proof of mechanism in both rat and mouse TNF-α challenge models.

Full text of DOI:10.1021/ml300175c

Letter
pubs.acs.org/acsmedchemlett
Identification of an Adamantyl Azaquinolone JNK Selective Inhibitor
Nancy-Ellen Haynes,* Nathan R. Scott, Li C. Chen, Cheryl A. Janson, Jia Kui Li, Christine M. Lukacs,
Aruna Railkar, Effie Tozzo, Toni Whittard, Nicholas F. Brown, and Adrian Wai-Hing Cheung
Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New
Jersey 07110, United States
S
* Supporting Information
ABSTRACT: 3-[4-((1S,2S,3R,5S,7S)-5-Hydroxyadamantan-2-ylcarbamoyl)benzyl]-4-
oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (4) was
identified as a novel, druglike and selective quinolone pan JNK inhibitor. In this
communication, some of the structure−activity relationship of the azaquinolone
analogues leading to 4 is discussed. The focus is on how changes at the amide
functionality affected the biochemical potency, cellular potency, metabolic properties,
and solubility of this class of JNK inhibitors. Optimization of these properties led to the
identification of the adamantyl analogue, 4. 4 achieved proof of mechanism in both rat
and mouse TNF-α challenge models.
KEYWORDS: JNK selective inhibitor, kidney disease, adamantyl azaquinolone
he c-jun NH2-terminal kinases (JNK-1, JNK-2, and JNK-
3) are members of the mitogen activated protein (MAP)
well as the identification of rapidly detectable and sensitive
biomarkers and the determination of appropriate physiological
and clinical end-points.9,10 Identification of selective com-
pounds will be important to help answer and guide the
biological investigation of this disease.
T
kinase family. Whereas JNK-1 and JNK-2 are ubiquitously
expressed throughout the body, JNK-3 is found primarily in the
brain, heart, and testes. The JNKs, also known as “stress
activated protein kinases”, are activated in response to a
number of natural stress stimuli, including reactive oxygen
species, UV light,1 and hypoxia,2,3 as well as some chemical
entities, such as the cancer drug Cisplatin.4 Activation of JNK
by internal or external stimuli can be detected in an
experimental setting by measuring phosphorylation of the
eponymous substrate c-jun.4
The JNK kinase family has attracted attention as a potential
target for multiple therapeutic indications such as rheumatoid
arthritis (RA), asthma, diabetes, and neurological disorders.5
JNK has also been shown to have increased activity in various
chronic kidney diseases and acute kidney injury (AKI).6 The
focus of our program was the development of novel JNK-
selective inhibitors that may be clinically effective in treating
AKI. AKI can have many different origins, but it is most
frequently encountered clinically as a complication of cardiac
surgery, as a consequence of sepsis, or as the nephrotoxic side-
effects of pharmaceutical agents including some chemo-
therapeutics, antibiotics, and nonsteroidal anti-inflammatory
drugs. AKI is a relatively common complication that can rapidly
lead to renal failure, which is associated with a high mortality
rate. Currently, no pharmaceutical agent has been approved for
the treatment of AKI. However, nonselective JNK inhibitors
(i.e., CC-401,7 SP6001258) have been shown to decrease
damage markers in rodent renal ischemia/reperfusion (I/R)
models and in Cisplatin nephrotoxicity studies.
An initial investigation of the quinolone series for the
indication of RA and asthma resulted in the identification of a
compound of interest, 1 (Figure 1).11 In our investigation of
inhibitors of JNK for the treatment of AKI, 1 was profiled, but
its potency in human kidney (HK-2) cells and microsomal
clearance values did not appear compelling to warrant further
profiling. The deficiencies of 1 were confirmed when it did not
achieve the necessary levels of JNK inhibition when challenged
with TNF-α in vivo (data not shown; the criteria used to
determine adequate inhibition of JNK will be described later in
this paper). Improved solubility was also a key challenge in
advancing the quinolones toward clinical candidate selection for
the indication of AKI. Since most AKI patients develop the
condition as a complication of surgery and are unable to take
medications orally, the preferred delivery route is intravenous
administration. Thus, it seemed there were few compounds
from the original exploration of the quinolone series which
presented adequate in vitro potency coupled with an acceptable
biopharmaceutical profile.11,12
However, closer examination of the structure−activity
relationship (SAR) from the RA/asthma program revealed an
underexplored subset of compounds, the 8-azaquinolones.12
A
number of compounds in the 8-aza series had been prepared
containing a 7-methyl group as in 2 (Figure 1). While inclusion
of a methyl vs a hydrogen at the 7-position imparted improved
Critical issues have impeded progress in the discovery of
agents to treat AKI. For example, there is increased debate over
the validity of available animal models and how these models
translate in terms of predicting efficacy in human disease, as
Received: June 28, 2012
Accepted: August 8, 2012
Published: August 8, 2012
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
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a
Table 1. (A) In Vitro Properties of 1, 4, and 6−11 ; (B) Oral
PK Parameters Obtained for 4, 6, and 8−11; (bottom) IV
b
PK Parameters Obtained for 4 and 9
Figure 1. Structures and properties of 1−5, showing mean values from
at least two experiments. HK-2 EC50:15 Cellular potency was
determined by the ability of compounds to prevent TNFα-stimulated
accumulation of phospho-c-jun in human proximal tubule (HK-2)
cells; LYSA solubility measurement (acetonitrile/water, 70:30, at 25
°C).
potency, it also resulted in decreased metabolic stability.12 Only
a single analog, 3, was synthesized with no substitution at the 7-
position in the original investigation of the azaquinolone series.
3 served as our starting point for SAR exploration in the AKI
indication with the goal of improving the solubility while
maintaining the in vitro and cellular potency.12 In this
communication, the results from the synthetic exercises to
probe the SAR of the azaquinolone series which led to 4 are
introduced. The main emphasis of this investigation involved
profiling various amides at the para position of the benzyl ring
(Table 1). This work culminated in the identification of 4, a
trans-hydroxyadamantyl azaquinolone isolated as the methanol
solvate.13,14 4 achieved a compromise between JNK bio-
chemical potency, cellular potency, solubility, and acceptable
rodent PK. Furthermore, no other kinases in a screen of >450
kinases were inhibited more than 50% at the testing
concentration of 10 μM (Supporting Information). This result
allowed us to conclude that the in vitro and in vivo activities
observed were most likely based solely on JNK activity and not
due to inhibition of other kinases (Cerep panel).
In order to help guide chemistry efforts and to try to
understand the exquisite selectivity of the quinolone/
azaquinolone based compounds, we determined the crystal
structures of JNK1β1-JIP with many of our compounds. Figure
2 shows the binding of a trans-aminoadamantyl azaquinolone, 5
to JNK1.
The backbone NH from methionine 111 in the kinase hinge
donates a hydrogen bond to the carbonyl of the azaquinolone,
and this is the only compound−hinge hydrogen bond
interaction. The conformation of the main chain of methionine
111 is quite unique among the kinases that we have observed.
Generally, the residue at this position is oriented such that the
backbone carbonyl points directly into the ATP binding site
a
MLM (mouse microsomes; mL/(min·kg)); l = low clearance
(<27.4); m = medium clearance (27.4-63.9); h = high clearance
(>63.9); mHep (mouse hepatocytes): l (<27.6), m (27.6−63.9), h
(>63.9). Mean values from at least two experiments. (B) Experiments
performed in C57 mice dosed po at 30 mg/kg; IV at 5 mg/kg; a: 20%
DMSO/80% PEG 400; b: 5% DMSO/30% PEG monooleate/65%
PEG 400. All numbers are the mean average (n ≥ 2).
b
and accepts a hydrogen bond from the ligand; it would clash
with a carbonyl from a small molecule. In the JNKs, this
backbone carbonyl is pointed more perpendicularly from the
cleft, allowing compounds such as the quinolones/azaquino-
lones to bind without clashing. We believe that this is the
primary basis for the excellent selectivity seen for this class.
The aryl chain then leads away from the ATP pocket. The
phenyl sits in a ∼8 Å wide hydrophobic channel flanked by the
side chain of isoleucine 32 and the peptide plane of aspartate
112/alanine 113 from the end of the hinge. The amide linked
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ACS Medicinal Chemistry Letters
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Scheme 1. General Scheme for the Synthesis of Amides in
a
the 8-Azaquinolone Series
a
Reagents and conditions: (a) N,O-hydroxylamine hydrochloride,
Figure 2. X-ray crystal structure of 5 with JNK1.
benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexafluoro-
phosphate, rt, 93%; (b) 3.0 M MeMgCl in THF, 0 °C, 72%; (c)
aniline, dl-10-camphorsulfonic acid, 1,4-dioxane, 80 °C, 36%; (d)
methyl-4-formylbenzoate, 25 wt % NaOMe in MeOH, rt, 95%; (e)
10% Pd/C, H2, EtOAc, CH2Cl2, rt, 81%; (f) methyl 2-chloro-2-
oxoacetate, toluene, 130 °C, used without further purification; (g)
K2CO3, MeOH, 85 °C; (h) EDC-HCl, HOBT, DIPEA, CH2Cl2, rt,
12−82%.
trans-adamantyl moiety then reaches the outside of the N-
terminal lobe of the kinase, generally making only hydrophobic
interactions with the protein. This shallow pocket where the
adamantyl sits may also represent another element that is
helpful for determining JNK selectivity: alanine 42, which is at
the base of this cleft, in other kinases is often a lysine, whose
side chain would fill and therefore eliminate the shallow pocket.
A general synthetic approach for the 8-aza analogs is shown
in Scheme 1.14 The synthesis of the azaquinolone scaffold was
initiated by synthesizing the Weinreb amide, I, of 2-
chloronicotinic acid followed by installation of the methyl
ketone by treatment with methyl Grignard. Displacement of the
chloride of II with aniline under acidic conditions provided III.
A subsequent aldol condensation resulted in the formation of
the α,β-unsaturated ketone, IV, which was ultimately reduced
under standard hydrogenation protocols. Installation of the
glyoxylate ester set up the system for base initiated cyclization
and dehydration with concomitant ester hydrolysis to the
azaquinolone core, VII. Amide formation under standard
conditions using various amines allowed exploration of the
SAR at this position via compounds such as VIII.
A set of amines identified from our lab shown to increase the
potency of the quinolone class in the biochemical assay were
coupled onto the p-benzoic acid position (Table 1A).12 The
values reported in Table 1 are the average of at least two
separate experiments, and it is typical for duplicate values to be
within 2-fold of each other.
This exercise resulted in many analogs which exhibited good
in vitro potency, high solubility (LYSA: lyophilized solubility
assay),16 and moderate microsomal stability. It appeared that
the changes in the amide functionality did not dramatically alter
the biochemical activity. However, these changes resulted in
significant changes in solubility, and as the solubility increased,
the cellular potency decreased noticeably.17 This trend is most
clearly observed by examining the data for 7−11. All have
comparable in vitro potencies, but the cellular potency suffered
as the solubility increased. An exception to this trend was 4. 4
exhibited moderate solubility and clearance, good in vitro
potency, and acceptable cellular potency. The properties of 4
can be contrasted to the original lead of the quinolone series, 1,
which exhibited lower in vitro and cellular potency, lower
solubility, and higher microsomal clearance (Table 1A).
To further delineate the differences between the analogs, PK
experiments were performed and tissue exposures were
measured (Table 1B). Analogs 4, 6, and 8−11, which exhibited
a range of cellular potencies, were dosed orally in mice at 30
mg/kg. Of these compounds, only 4, 8, and 9 exhibited
adequate plasma and kidney exposure (Table 1B). Based on the
PK results, although 4, 6, and 8−11 exhibited moderate to high
clearance in microsomes, it was shown that the hepatocyte data
correlated better with in vivo clearance (Table 1A).
An IVPK was performed on 4 and 9 to compare clearance
and AUC parameters (Table 1B). Since the PK parameters of 4
and 9 were quite similar, the decision to further investigate 4
was based on its overall profile. Only 4 combined good
exposure numbers with an acceptable cellular potency in HK-2
cells (4.1 μM). It appeared that 4, isolated as the methanol
solvate, provided a molecule that attained a balance between
solubility and cellular activity while moderating microsomal
clearance.13,17 Based on these results, further profiling of 4 was
pursued.
Due to limited solubility of the quinolone series in general, a
DMSO-containing formulation was used to profile the PK
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ACS Medicinal Chemistry Letters
Letter
a
Table 2. Oral and IV PK Parameters Obtained for 421
Oral PK
species
rat
formulation
dose (mg/kg)
Cmax (ng/mL)
AUC (h·ng/mL)
tmax (h)
t1/2 (h)
DMSO
DMSO
MBP
30
30
75
75
8030
13600
48300
22400
252000
49200
4.0
2.4
C57 mouse
rat
0.25
4.0
30100
2.0
C57 mouse
MBP
18100
1.0
1.62
IV PK
species
formulation
dose (mg/kg)
CL (mL/min/kg)
Vd (L/kg)
AUC extrap. (h·ng/mL)
MRT (h)
t1/2 (h)
rat
DMSO
DMSO
5
5
6.4
8.4
0.61
0.30
16310
9890
1.8
0.6
2.4
0.6
mouse
a
Compound was dosed orally to noncannulated rodents. DMSO: 20% DMSO, 80% PEG 400 solution. MBP: 20% drug loading, 2% Klucel in water
pH 4.0. IV formulation strength: 1 mg/mL. DMSO: 5% DMSO, 20% PEG 400, HPBCD in water. All numbers are the mean average (n ≥ 2).
properties of compounds initially. This formulation allowed a
larger set of analogs to be studied. However, DMSO itself can
have protective effects on the kidney in rodent models of AKI,
and thus, its use could confound the interpretation of results
obtained in disease models.18,19 The DMSO based formulation
was replaced with an amorphous formulation, MBP (micro-
precipitated bulk powder).20 The PK experiments performed
with 4 in rats and mice using the DMSO-based and MBP
formulations are shown in Table 2. Several important points
emerged from these PK experiments. First, in either
formulation, clearance was comparable in the mouse and in
the rat. Second, the MBP formulation resulted in comparable,
or superior, PK to that seen using the DMSO-containing
formulation. Third, when the rat was dosed at 75 mg/kg in
MBP with 4, the exposure was maintained for over 8 h at a level
2-fold higher than the predicted EC50, a level predicted to effect
a significant inhibition of kidney JNK (Supporting Informa-
tion).
To confirm this prediction, we performed “proof of
mechanism” (POM)22 experiments using 4 in the rat, based
on a TNF-α challenge model. In this paradigm, rats were dosed
with 4 (or vehicle) followed some time later by intravenous
administration of TNF-α (2.5 μg/kg), which causes JNK
activation in multiple tissues, including the kidney. A control
group received only saline IV. Thus, by quantifying the
accumulation of p-c-jun in the kidney 1 h after TNF-α/saline
(by Western blot), it was possible to estimate the degree of
JNK inhibition achieved. Figure 3 shows that when TNF-α was
dosed 7 h after 4, p-c-jun accumulation in the kidney was only
52% of the level in rats that did not receive 4. This significant
reduction of signal confirmed the prediction based on the PK.
Since the degree of JNK inhibition required for efficacy in
disease models is unknown, it was important to establish a
dosing regimen that would significantly inhibit kidney JNK for
24 h. Thus, we repeated the TNF-α challenge in rat, dosing 4 at
0 and 12 h (bid dosing) or 0, 8, and 16 h (tid dosing), with the
TNF-α introduced at 23 h. At 24 h, the kidneys were harvested,
and the results for p-c-jun content are shown in Figure 3. The
data demonstrated that, with multiple dosing, significant
continuous inhibition of kidney JNK was achieved.
In summary, a pan JNK selective azaquinolone analogue, 4,
showing promising in vitro and biopharmaceutical properties
was identified. From PK studies, 4 exhibited higher kidney and
plasma exposure in rats than in mice. MBP formulation of 4
with dosing at 75 mg/kg in rat provided sufficient drug
exposure at the 8 h time point to significantly blunt TNF-α
induced c-jun phosphorylation in kidney. The results shown for
Figure 3. 4 lowered kidney p-c-jun at 8 h in the TNF-α challenge
model in rat. 75 mg/kg po in MBP formulation. *p < 0.05 relative to
TNF-α alone.
4 serve to clarify the differences in potency and properties
between 4 and the RA/asthma lead, 1. Although 1 and 4 were
members of the same quinolone series, 4 exhibited enhanced
biopharmaceutical properties, improved potency for the AKI
indication, and achieved POM for JNK inhibition in the TNF-α
challenge model. Incorporation of the trans-hydroxyadamantyl
moiety into the azaquinolone series and isolation of its
methanol solvate provided the key to obtaining a balance
between the biochemical, in vitro, and in vivo properties.13
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures, crystallographic methods,
kinase selectivity data, and assay data. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
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ACS Medicinal Chemistry Letters
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(9) Parikh, C. R.; Devarajan, P. New biomarkers of acute kidney
injury. Crit. Care Med. 2008, 36 (4), S159−S165.
AUTHOR INFORMATION
Corresponding Author
*Telephone: 973-235-6409. Fax: 1-973-235-6389. E-mail:
nancy-ellen.haynes@roche.com.
■
(10) Coca, S. G.; Parikh, C. R. Urinary biomarkers for acute kidney
injury: Perspectives on translation. Clin. J. Am. Soc. Nephrol. 2008, 3,
481−490.
Notes
(11) Gong, L.; Tan, C.; Boice, S. A.; Mclan, K.; Wong, B.; Jin, S.;
Chiang, A.; Tran, P.; Goldstein, D.; Kuglstatter, A. Discovery of a
novel series of 4-quinolone JNK inhibitors. Bioorg. Med. Chem. Lett.,
submitted.
(12) Abbot, S.; Boice, G.; Buettelmann, B.; Goldstein, D. M.; Gong,
L.; Hogg, J. H.; Iyer, P.; McCaleb, K. L.; Tan, Y.-c. WO138920A1,
2008.
(13) Anderson, K. W.; Fotouhi, N.; Gillespie, P.; Goodnow, R. A., Jr.;
Guertin, K. R.; Haynes, N.-E.; Myers, M. P.; Pietranico-Cole, S. L.; Qi,
L.; Rossman, P. L.; Scott, N. R.; Thakkar, K. C.; Tilley, J. W.; Zhang,
Q. WO107470A2, 2007.
(14) Cheung, A.; Guertin, K. R.; Haynes, N.-E.; Mertz, E.; Scott, N.
R.; Qi, L.; Qian, Y. Patent filed April 2011.
(15) The cell-based assay employed the in-cell ELISA method to
determine the ability of compounds to prevent the generation of
phospho(Ser63)-c-jun in HK-2 cells (human proximal tubule cells) in
response to stimulation with tumor necrosis factor α (TNF-α). The
values reported are the average of at least two separate experiments,
and it is typical for duplicate values to be within 2-fold of each other.
(16) Henchoz, Y.; Bard, B.; Guillarme, D.; Carrupt, P.-A.; Veuthey, J.-
L.; Martel, S. Analytical tools for the physiochemical profiling of drug
candidates to predict absorption/distribution. Anal. Bioanal. Chem.
2009, 394, 707−729.
(17) HK-2 cellular assay: stimulates or stresses the cell by applying
TNF-α (an established cytokine/stressor known to stimulate JNK);
dose compound; measure how well the drug/compound blunts the
excursion of TNF-α by measuring the amount of c-jun phosphor-
ylation present relative to rats exposed to vehicle.
(18) Hoyos, W.; Medina, I.; Lopez, R.; Ramos, J.; Garcia, Z.; Lopez,
S. 29th International Symposium on Intensive Care and Emergency
Medicine. Crit. Care 2009, 13 (Suppl 1), S149.
(19) Lind, R. A.; Gandolfi, A. J. Late dimethyl sulfoxide
administration provides a protective action against chemically induced
injury in both liver and the kidney. Toxicol. Appl. Pharmacol. 1997,
142, 201−207.
(20) Albano, A. A.; Phuapradt, W.; Sandhu, H. K.; Shah, N. H. U.S.
Patent 6350786B1, 2002.
(21) Aliquots (0.025 mL) of rodent plasma were protein precipitated
with acetonitrile. The extracts were diluted with water and analyzed by
LC/MS/MS.
(22) POM experiment: in vivo measurement of how well the drug/
compound blunts the excursion of TNF-α by measuring the amount of
c-jun phosphorylation present relative to rats exposed to vehicle; proof
of mechanism.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the entire JNK team for their dedication to
the project: Bruce Banner, Joseph Bilotta, Mark Dvorozniak,
Lin Gao, Kevin Guertin, Stuart Hayden, Kuo-Sen Huang, Xilin
Liu, Mahmoud Loghman-Adham, Nick Marcopulos, Eric
Mertz, Anjula Pamidimukkala, Frank Podlaski, Lida Qi, Yimin
Qian, Cristina Rondinone, Joseph Sergi, Sung-Sau So, Kshitij
Thakkar, Jefferson Tilley, and Yang Wen. We would also like to
acknowledge Stephen Wasserman and Sunal Sojitra at LRL-
CAT for X-ray data collection, and Linda Reik for protein
purification.
ABBREVIATIONS
■
JNK, c-jun NH2-terminal kinase; RA, rheumatoid arthitis; AKI,
acute kidney injury; I/R, ischemia/reperfusion; SAR, structure
activity relationship; HK-2 cells, human kidney cells; TNF-α,
tumor necrosis factor-α; LYSA, lyophilized solubility assay; JIP,
JNK interacting protein; ATP, adenosine triphosphate; THF,
tetrahydrofuran; EDC-HCl, N-(3-dimethylaminopropyl)-N′-
ethylcarbodiimide hydrochloride; DIPEA, N,N-diisopropylethyl
amine; HOBT, N-hydroxybenzotriazole; EtOAc, ethyl acetate;
DMSO, dimethyl sulfoxide; PEG, polyethylene glycol; IV,
intravenous; PK, pharmacokinetics; MBP, microprecipitated
bulk powder; MRT, mean residence time; MLM, mouse liver
microsomes; AUC, area under the curve; Vdss, volume of
distribution; mHEP, mouse hepatocyte; HPBCD, hydroxy-
propyl-beta-cyclodextrin
REFERENCES
■
(1) Derijard, B.; Hibi, M.; Wu, I. H.; Barrett, T.; Su, B.; Deng, T.;
Karin, M.; Davis, R. J. JNK1: A protein kinase stimulated by UV light
and Ha-Ras that binds and phosphorylates the c-Jun activation
domain. Cell 1994, 76, 1025−1037.
(2) Kuan, C. Y.; Whitmarsh, A. J.; Yang, D. D.; Liao, G.; Schloemer,
A. J.; Dong, C.; Bao, J.; Banasiak, K. J.; Haddad, G. G.; Flavell, R. A.;
Davis, R. J.; Rakic, P. A critical role of neural-specific JNK3 for
ischemic apoptosis. Proc. Natl. Acad. Sci. U.S.A. 2003, 100 (25),
15184−15189.
(3) Pirianov, G.; Brywe, K. G.; Mallard, C.; Edwards, A. D.; Flavell, R.
A.; Hagberg, H.; Mehmet, H. Deletion of the c-Jun N-terminal kinase
3 gene protects neonatal mice against cerebral hypoxic-ischaemic
injury. J. Cereb. Blood Flow Metab. 2007, 27, 1022−1032.
(4) LoGrasso, P.; Kamenecka, T. Inhibitors of c-jun-n-Terminal
Kinase (JNK). Mini-Rev. Med. Chem. 2008, 8, 755−766.
(5) Cui, J.; Zhang, M.; Zhang, Y.-Q.; Xu, Z-h. JNK pathway: diseases
and therapeutic potential. Acta Pharmacol. Sin. 2007, 28, 601−608.
(6) De Borst, M. H.; Prakash, J.; Melenhorst, W. B. W. H.; van den
Heuvel, M. C.; Kok, R. J.; Navis, G.; van Goor, H. Glomerular and
tubular induction of the transcription factor c-Jun in human renal
disease. J. Pathol. 2007, 213, 219−228.
(7) Kanellis, J.; Ma, F. Y.; Kandane-Rathnayake, R.; Dowling, J. P.;
Polkinghorne, K. R.; Bennett, B. L.; Friedman, G. C.; Nikoloc-
Paterson, D. JNK signaling in human and experimental renal
ischaemia/reperfusion injury. Nephrol. Dial. Transplant 2010, 25,
2898−2908.
(8) Wang, Y.; Ji, H.-X.; Pei, D.-S.; Guan, Q.-H. SP600125, a selective
JNK inhibitor, protects ischemic renal injury via suppressing the
extrinsic pathways of apoptosis. Life Sci. 2007, 80, 2067−2075.
768
dx.doi.org/10.1021/ml300175c | ACS Med. Chem. Lett. 2012, 3, 764−768