Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

Article abstract of DOI:10.1016/j.bmcl.2009.06.058

A novel class of fused pyrazole-derived inhibitors of p38α mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38α enzyme, the secretion of TNFα in a LPS-challenged THP1 cell line and TNF

Full text of DOI:10.1016/j.bmcl.2009.06.058

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4724–4728
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Part 1: Structure–Activity Relationship (SAR) investigations of fused
pyrazoles as potent, selective and orally available inhibitors of p38
mitogen-activated protein kinase
a
a
a
b
b
b
Ryan P. Wurz a, , Liping H. Pettus , Shimin Xu , Bradley Henkle , Lisa Sherman , Matthew Plant ,
Kent Miner b, Helen McBride b, Lu Min Wong b, Christiaan J. M. Saris b, Matthew R. Lee c,
Samer Chmait c, Christopher Mohr c, Faye Hsieh d, Andrew S. Tasker a
*
a Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
b Department of Inflammation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
c Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
d Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of fused pyrazole-derived inhibitors of p38
disclosed. These inhibitors were evaluated for their ability to inhibit the p38
a
mitogen-activated protein kinase (MAPK) is
enzyme, the secretion of
a-induced production of IL-8 in 50% human whole blood.
Received 20 May 2009
Revised 11 June 2009
Accepted 15 June 2009
Available online 17 June 2009
a
TNF in a LPS-challenged THP1 cell line and TNF
a
This series was optimized through a SAR investigation to provide inhibitors with IC50 values in the low
single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles
led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor
10m was found to be efficacious in vivo in the inhibition of TNF
with an ED50 of 0.1 mg/kg while 10q was found to have an ED50 of 0.05–0.07 mg/kg.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
p38
MAP kinase
TNF
a production in LPS-stimulated Lewis rats
Pyrazolopyridinone
Rheumatoid arthritis (RA) is a chronic and systemic inflamma-
tory disease characterized by inflammation and progressive joint
deterioration. Recently, biologics such as EnbrelÒ (etanercept),
RemicadeÒ (infliximab), HumiraÒ (adalimumab), and KineretÒ
(anakinra) have demonstrated clinical efficacy in the treatment of
of TNF
cells to the site of inflammation.
p38 exists in four isoforms (
each isoform varies among different cell types of the immune sys-
tem. The p38 isoform is believed to be the most clinically relevant
for the treatment of RA,4 hence, p38
has emerged as an attractive
target for small molecule drug discovery to blockade the action of
TNFa 5
a among other cytokines and the migration of white blood
a, b, c, and d) and expression of
a
RA.1 These protein therapeutics act by blocking the action of TNF
a
a
or IL-1 and are significant therapeutic advances for the treatment
of these often debilitating conditions.
.
The development of orally active small molecule inhibitors to
modify the proinflammatory cytokine release associated with RA
represents an attractive alternative due to drawbacks related to pa-
tient cost, and administration associated with biologics.2 p38 mito-
Amgen recently disclosed a series of phthalazine-derived p38
inhibitors6 which were found to be highly potent in cell-based as-
says and efficacious in the rat collagen induced arthritis (CIA) mod-
el. Although these inhibitors exhibited exceptional selectivity for
gen-activated protein kinase (MAPK) is
intracellular family of MAP kinases implicated in the phosphoryla-
tion cascade leading to the release of TNF and other cytokines
including interleukin-1beta (IL-1b), interleukin-6 (IL-6) and inter-
leukin-8 (IL-8). p38 kinases are activated by a variety of stress
stimuli including osmotic shock, ionizing radiation, mechanical
wear, and cytokine stimulation.3 Activation results in the release
a
member of the
p38ab over other kinases, the future goal of the program was to
further improve upon this selectivity in addition to reducing brain
exposure (data not shown). Herein, the discovery and exploratory
structure–activity relationship (SAR) study of a novel pyrazolopy-
ridinone chemotype (1) is described (Fig. 1).
Inspiration for this scaffold was based on recent reports of p38
inhibitors containing a benzamide unit linked to a heterocycle via
an aniline nitrogen (Fig. 2). The first of these reports contained a
benzamide tethered to a triazine scaffold (2, Fig. 2).7 In subsequent
disclosures, the triazine moiety was replaced with various
other heteroaromatic groups including 5-cyanopyrimidines (3),8
a
* Corresponding author. Tel.: +1 805 313 5400; fax: +1 805 480 1337.
E-mail address: rwurz@amgen.com (R.P. Wurz).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.058

R. P. Wurz et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4724–4728
4725
R1
X
H
N
CO2Et
NH2
CO2Et
Ac
HCl.NH2
EtO
Ar
H
i
ii-iii
iv
N
R2
N
N
CN
CO2Et
N
N
Ar
6
N
Ar
7
O
H
N
X = NH, O
N
N
R
O
1
Ar
R2
Cl
X
CO2Et
Ac
Figure 1. Pyrazolopyridinone-derived p38 inhibitors.
v-vi
vii
N
N
N
N
N
N
N
R1
O
R1
N
N
R1
O
Ar
Ar
4-(phenylamino)-pyrrolo[2,1-f][1,2,4] triazines (4)9 and more
recently pyrazolopyrimidines (5).10
Ar
8
9
10
The compounds necessary for our SAR investigation were pre-
pared in seven steps via the general route illustrated in Scheme
1. Thus, suitably functionalized pyrazoles (6) were readily pre-
pared in excellent yields (70–99%) upon treatment of an aryl
hydrazine with ethyl (ethoxymethylene) cyanoacetate.11 Amine
bis(acetylation) followed by mono-deprotection using ethanolic
potassium hydroxide at room temperature afforded the 5-amino-
pyrazole monoacetate (7) which could be N-alkylated using the de-
sired halide (R1X) (33–82% yield over three steps).12 A variety of
bases13 were then examined for the construction of the pyridinone
ring through an intramolecular cyclization. Ultimately, lithium di-
isopropyl amide (LDA) was found to be the most effective base to
achieve this cyclization (35–99%). Chlorination of the 4-hydrox-
ypyridinone cyclization product using phosphorus oxychloride14
furnished the common chloride coupling partner in modest yields
(9, 23–75%). Subsequent Buchwald–Hartwig amination with the
desired aniline afforded analogues 10 (X = NH) in moderate yields
(15–87%)15 while Buchwald etherification with phenols yielded the
corresponding ether analogues 10 (X = O) in low to moderate
yields (20–60%).16
Scheme 1. General synthetic route used to access aniline NH- and O-linked
pyrazolopyridinone benzamides. Reagents and conditions: (i) Et3N, EtOH, 90 °C; (ii)
Ac2O, DMAP, Et3N, 1,2-DCE, reflux; (iii) KOH, EtOH, rt; (iv) NaH, LiBr, R1X, 10:1
DME:DMF; (v) LDA, THF, À78 °C to rt; (vi) POCl3, 100 °C; (vii) X = NH: Pd2(dba)3,
Dave-Phos, R2NH2, LiHMDS, THF, 60 °C; X = O: Pd2(dba)3, t-Bu2X-Phos, R2OH, K3PO4,
PhMe:THF 5:1, lwave, 120 °C.
nanomolar range in hWB (10e–h). The sterically demanding tert-
butyl amide (10i) exhibited a 100-fold reduction in potency in
the TNFa/IL-8 assay in hWB compared to the cyclopropyl amide
analogue 10h. Replacement of the amide with a carboxylic acid
(10j) led to loss of enzyme and cell-based potency, illustrating
the importance of the amide in this position.
SAR was then directed to further optimization of the scaffold
while conserving the cyclopropylamide18 portion of the benzamide
motif (Table 2). The fluorine substitution pattern on the aryl group
at the N-1 position of the pyrazolopyridinone ring had little influ-
ence on IC50 values in hWB, varying from 1.3–2.5 nM across a ser-
ies (e.g., 10k,h,u,y). Replacement of the benzamide ortho-tolyl
group (R3 = Me) with an ortho-chloro group (R3 = Cl) also resulted
in potent compounds (e.g., 10m,q,v,z). In contrast, introduction
of a fluorine atom (R3 = F) at this position resulted in a >4-fold
reduction in hWB potency (e.g., 10s,aa) as compared to R3 = Me.
Modifying the R1-substituent from a methyl group to an ethyl
group was well tolerated (e.g., 10n–p,r).19
The preliminary SAR focused on optimization of R2. The com-
pounds were tested for their ability to inhibit p38
the phosphorylation of ATF2), as well as their potency in lipopoly-
saccharide (LPS) challenged TNF production in a THP1 cell line
a (by monitoring
a
and in TNFa stimulated IL-8 secretion in 50% human whole blood
(hWB, Table 1).17
Compounds with R2 groups such as tetrahydropyran (10a) or
Replacement of X = NH to X = O generally resulted in a sizable
erosion in THP1 and hWB potency. This is possibly attributed to
the decline in solubility of these compounds.20 One exception to
this trend was compound 10ab which retained low single-digit
nanomolar potency in the cellular assays.
fluorinated aryl groups (10b–c) were inactive against p38
duction of a 3-substituted-4-methyl-pyridine motif at R2 (10d) re-
sulted in weak inhibition of p38 . Incorporation of an ortho-tolyl
benzamide as R2 provided several compounds which were potent
a. Intro-
a
inhibitors of p38
a
and exhibited IC50 values in the low single-digit
In light of their excellent cellular potencies, a series of com-
pounds were profiled for their pharmacokinetic (PK) parameters
in order to differentiate these compounds for further studies (Table
3). With the exception of compounds 10g and 10z, all of the com-
pounds demonstrated low to moderate clearance. However, com-
pounds 10m and 10q stood apart as they displayed good
exposure (AUC) and excellent oral bioavailability (%F) following
oral dosing at 2 mg/kg.
H
H
N
HN
O
N
N
HN
N
O
O
N
N
NC
HN
O
N
N
N
N
The X-ray co-crystal structure of 10h bound to unphosphory-
a
(Fig. 3)21 revealed several key binding interactions.
2
3
lated p38
N
The NH of the Met109 linker residue engages in a hydrogen bond-
ing interaction with N-2 of the pyrazolopyridinone scaffold (3.2 Å)
while the N-1 aryl group is projected into a hydrophobic pocket
H
H
N
near the hinge region of the p38
a enzyme. This aryl group is
N
N
HN
HN
N
O
skewed with respect to the pyrazolopyridinone scaffold as previ-
ously reported.10 The floor of this hydrophobic pocket contains
an Ala157 residue, which is smaller than the corresponding residue
in over 98% of the kinome.22 This residue engages in a tight van der
Waals contact with the 2-fluorophenyl substituent (3.4 Å), thereby
providing a structure-based approach for enhancing selectivity
over other kinases. The ‘gate-keeper’ residue, Thr106, is internally
O
O
O
N
N
N
N
HN
N
N
Ph
4
5
Figure 2. Examples of Bristol-Myers Squibb p38 inhibitors containing an aniline N-
linked benzamide motif.

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R. P. Wurz et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4724–4728
Table 1
SAR of modifications to Ar and R2a
R2
HN
N
N
N
O
Ar
10
IC50 (nM)
Compd
Ar
R2
p38a
THP1 LPS/TNF
a
IC50 (nM)
hWB TNFa/IL-8 IC50 (nM)
10a
3-F-Ph
>1000
>2500
>2500
O
10b
10c
10d
10e
10f
10g
10h
10i
2,6-Di-F-Ph
2,4-Di-F-Ph
2,5-Di-F-Ph
2,4-Di-F-Ph
2,5-Di-F-Ph
2,4-Di-F-Ph
2,4-Di-F-Ph
2,4-Di-F-Ph
2,4-Di-F-Ph
>1000b
>1000b
444b
2.6b
546b
937b
208b
1.9
>833
>2500
403
3.4
F
F
F
N
NH2
NH2
O
3.7b
7.5
7.1
O
O
O
H
N
1.1
1.1
1.4
OMe
H
3.2b
1.0
2.4
N
H
269b
65b
204
>2500
N
O
>2500b
OH
10j
>1000
O
a
The IC50 data are mean values derived from at least three independent dose–response curves. Variability around the mean value was <50%.
Data represents an average of two dose–response curves.
b
hydrogen-bonded to the carbonyl of His107 while the oxygen lone
ylate of Asp168 and Lys53 through a network of hydrogen bonds.
The ‘DFG in’ configuration (residues Asp168, Phe169, Gly170) is
observed as expected.23
Compounds 10m and 10q were screened against a panel of 60
kinases for potential off-target liabilities.24 While compound 10m
showed no selectivity over p38b (IC50 = 4 nM), it was very selective
pair participates in a hydrogen bond with the aniline NH (3.0 Å).
The cyclopropyl amide forms two key interactions with Asp168
and Glu71. The amide carbonyl forms a hydrogen bond to the NH
of Asp168 (2.9 Å) while the carboxylate of Glu71 forms a hydrogen
bond with the NH of the cyclopropyl amide (3.0 Å). Another feature
of the binding of this inhibitor is the presence of two water mole-
cules which serve to bridge the pyridinone carbonyl to the carbox-
against p38c, p38d isoforms and JNK1-3 (IC50 values >10 lM). It
also showed some inhibitory activity against c-Raf (40% POC at

R. P. Wurz et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4724–4728
4727
Table 2
SAR of modifications to R1, R3 and Ara
R3
H
N
X
O
N
N
N
R1
O
Ar
10
Compd
Ar
R1
R3
X
p38
a
IC50 (nM)
THP1 LPS/TNF
a
IC50 (nM)
hWB TNFa/IL-8 IC50 (nM)
10k
10l
3-F-Ph
3-F-Ph
4-F-Ph
4-F-Ph
4-F-Ph
4-F-Ph
2,4-Di-F-Ph
2,4-Di-F-Ph
2,4-Di-F-Ph
2,4-Di-F-Ph
2,4-Di-F-Ph
2,5-Di-F-Ph
2,5-Di-F-Ph
2,5-Di-F-Ph
2,5-Di-F-Ph
2,6-Di-F-Ph
2,6-Di-F-Ph
2,6-Di-F-Ph
2,6-Di-F-Ph
Me
Me
Me
Et
Et
Et
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Cl
Me
Cl
Me
Me
Cl
NH
O
NH
NH
NH
O
NH
NH
NH
NH
O
NH
NH
O
3.3b
8.5
1.3
12
1.7
29
2.5
1.9
0.93
13
2.4
1.1
1.3
19
10m
10n
10o
10p
10h
10q
10r
1.5
1.1
1.1
1.0
1.8
1.0
0.44
0.67
6.7
3.5
1.0
1.1
5.0
14
4.0b
1.2
4.0
3.2b
1.0
Cl
F
1.1
10s
10t
13b
7.8b
2.9b
1.1
Me
Me
Cl
Me
Cl
Me
Cl
F
16
10u
10v
10w
10x
10y
10z
10aa
10ab
2.5
1.9
16
6.1b
3.3b
1.9b
1.1b
1.9
O
79
NH
NH
NH
O
0.87
0.62
3.2
1.0
1.3
1.5
8.2
2.6
Me
1.4
a
The IC50 data are mean values derived from at least three independent dose–response curves. Variability around the mean value was <50%.
Data represents an average of two dose–response curves.
b
Table 3
Mean pharmacokinetic parameters for a series of compounds in male Sprague–
Dawley ratsa
Compd
iv (2.0 mg/kg in DMSO)
po (2.0 mg/kg)b
CL ((L/h)/kg)
Vdss (L/kg)
t1/2 (H)
AUC(0-inf.) (ng.h/mL)
F (%)
10g
10m
10o
10p
10q
10r
10v
10y
10z
10ab
2.6
1.7
0.97
1.8
1.1
1.2
1.5
1.2
1.2
1.9
1.3
3.3
5.8
3.7
3.2
3.8
3.4
2.1
2.8
3.4
2.3
120
6547
2293
1496
4612
776
2163
273
139
15
84
45
41
81
16
56
12
9
0.26
0.41
0.27
0.37
0.42
0.52
0.88
1.3
0.63
244
7
a
Values are for an average of three rats.
b
Vehicle: 1% Pluronic F68, 1% HPMC, 15% hydroxypropyl b-cyclodextrin, 83%
water.
Figure 3. X-ray co-crystal structure of compound 10h with unphosphorylated
p38
a.
1.5
lM). Compound 10q displayed a very similar selectivity profile
to that of 10m (c-Raf 75% POC at 1.5
l
M). Compound 10m was 97%
and resulted in an ED50 of ca. 0.1 mg/kg for compound 10m (Fig. 4)
and an ED50 of ca. 0.05–0.07 mg/kg for compound 10q (Fig. 5). The
plasma exposure at the ED50 is 3.2 ng/mL for compound 10m and
estimated to be between 0.9 and 1.3 ng/mL for compound 10q. Com-
pounds 10m and 10q were also found to have very low brain to plas-
ma ratios of 0.04 and 0.06, respectively.
and 94% bound to rat and human plasma protein, respectively
(determined by ultrafiltration methods) while compound 10q
was 98% and 96% bound to rat and human plasma protein, respec-
tively. Compound 10m showed little inhibition of CYP 450 iso-
forms with 3A4 and 1A2 (IC50 >30
(IC50 >21 M). Compound 10q did have a CYP 450 liability with
2C9 (IC50 8.4 M). Two other isoforms were tested and found to
be satisfactory with 2C19 (IC50 16 M), and 2D6 (IC50 22.7 M).
lM) and 2C9, 2C19 and 2D6
l
In conclusion, through SAR studies a novel class of pyrazolopy-
ridinone p38 inhibitors has been identified. Compounds from this
l
l
l
series show excellent potency against p38a, in THP1 cell-based as-
Based on their suitable PK and selectivity profiles, compounds
10m and 10q were advanced to in vivo studies. The in vivo efficacy
of compounds 10m and 10q were demonstrated in an animal disease
says and in TNF challenged IL-8 secretion assays in 50% hWB.
a
Pharmacokinetic profiling also revealed that inhibitors 10m and
10q were orally bioavailable and displayed low iv clearance. Com-
pounds 10m and 10q were evaluated in vivo and found to inhibit
model of LPS induced TNF
compounds were administered at 0.01, 0.03, 0.1, and 0.3 mg/kg
a
production in female Lewis rats.25 Both

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R. P. Wurz et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4724–4728
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Figure 4. Effect of 10m on LPS induced TNF
Vehicle or compound was dosed po 60 min prior to injection with LPS IV (100
rat). Blood was collected 90 min later. Serum TNF
(Biosource). Data points represent mean STE (n = 6 rats/group): (*) p <0.01 versus
a
production in female Lewis rats.
g/
levels were determined by ELISA
l
a
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13. Other bases such as KOt-Bu were found not to promote this cyclization, see:
Sherlock, M. H.; Kaminski, J. J.; Tom, W. C.; Lee, J. F.; Wong, S.-C.; Kreutner, W.;
Bryant, R. W.; McPhail, A. T. J. Med. Chem. 1988, 31, 2108.
14. (a) Blackburn, C.; LaMarche, M. J.; Brown, J.; Che, J. L.; Cullis, C. A.; Lai, S.;
Maguire, M.; Marsilje, T.; Geddes, B.; Govek, E.; Kadambi, V.; Doherty, C.;
Dayton, B.; Brodjian, S.; Marsh, K. C.; Collins, C. A.; Kym, P. R. Bioorg. Med. Chem.
Lett. 2006, 16, 2621; b McCarthy, J. R. WO 98/35967, 1998.
15. Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7, 3965.
16. Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem., Int. Ed.
2006, 45, 4321.
17. For a description of the experimental details of the biological assays, see: Ref. 6.
18. The cyclopropyl amide was chosen for further optimization due to its favorable
PK profile when compared to the methoxy and primary amides.
19. A more extensive SAR investigation surrounding the nature of the aryl group at
N-1 and the R1-substituent will be reported in due course on a related class of
pyrazolopyridinone p38 inhibitors, in preparation.
20. The solubility data for compounds 10m,q,t,v,x in 0.01 N HCl were 31.2, 67.1,
Figure 5. Effect of 10q on LPS induced TNF
Vehicle or compound was dosed po 60 min prior to injection with LPS IV (100
rat). Blood was collected 90 min later. Serum TNF levels were determined by ELISA
(Biosource). Data points represent mean STE (n = 6 rats/group): (*) p <0.01 versus
vehicle control.
a
production in female Lewis rats.
5.7, 28.6 and 24.8
were found to be 26.6, 60.6, 5.3, 24.9, and 14.7
simulated intestinal fluid they were found to be 38.8, 81.7, 12.2, 35.2 and
49.0 g/mL, respectively.
l
g/mL, respectively, while in phosphate buffer saline they
lg/
l
g/mL, respectively, and in
a
l
21. The X-ray coordinates have been deposited in the RCSB Protein Data Bank
database (RCSB ID code: RCSB051790 and PDB ID code: 3GFE). We also thank the
Advanced Light Source staff at beamline 5.0.2 for their support. The Advanced
Light Source is supported by the Director, Office of Science, Office of Basic Energy
Sciences, Materials Sciences Division, of the U.S. Department of Energy under
Contract DE-AC03-76SF00098 at Lawrence Berkeley National Laboratory.
22. Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. Science
2002, 298, 1912.
the LPS induced production of TNFa with ED50’s of 0.1 mg/kg and
ca. 0.05–0.07 mg/kg, respectively.
Acknowledgments
23. For a leading references and examples on ‘DFG in’ versus ‘DFG out’, See: (a)
Bukhtiyarova, M.; Karpusas, M.; Northrop, K.; Namboodiri, H. V. M.;
Springman, E. B. Biochemistry 2007, 46, 5687; (b) Angell, R. M.; Angell, T. D.;
Bamborough, P.; Bamford, M. J.; Chung, C.-W.; Cockerill, S. G.; Flack, S. S.; Jones,
K. L.; Laine, D. I.; Longstaff, T.; Ludbrook, S.; Pearson, R.; Smith, K. J.; Smee, P. A.;
Somers, D. O.; Walker, A. L. Bioorg. Med. Chem. Lett. 2008, 18, 4433.
24. Kinase profiling on all kinases were tested at their apparent Km of ATP, using
We acknowledge Randall Hungate and Terry Rosen for their
support.
References and notes
1.5
JNK(1,2,3), JAK2, b-RAF, c-RAF, MAPKAPK2, KDR, SYK, RSK1, PI3 K(
SRC, Aur(A), c-Met, PIM2, ABL, FYN, LYN, AKT(1,2), CHK(1,2), Erk(1,2), FLT3,
GSK3b, ROCK2, PAK2, PKG , MST2, INSR, MSK1, PKCb2, CDK2, MARK1, IGF1R,
FGFR1, PKAC , PRAK, PKD2, CK1d, PKCz, TAK1, DYRK1 , CAMK(2,4), AMPK,
HGK, p70S6 K, IRAK4, SGK1, BTK, PDGFRb.
l
M inhibitor. The kinase selectivity panel included p38(
a
, b,
c
, d), c-KIT,
1. (a) Keystone, E. C. Rheu. Dis. Clin. North Am. 2001, 27, 427; (b) Seymour, H. E.;
Worsley, A.; Smith, J. M.; Thomas, S. H. L. Br. J. Clin. Pharmacol. 2001, 51, 201; (c)
Anon Physicians’ Desk Reference, 54th ed.; Medical Economics: Montvale, 2000.
pp. 927–1413.
2. Stanczyk, J.; Ospelt, C.; Gay, S. Curr. Opin. Rhe. 2008, 20, 257.
3. (a) Margutti, S.; Laufer, S. A. ChemMedChem 2007, 2, 1116; (b) Schett, G.;
Zwerina, J.; Firestein, G. Ann. Rhe. Dis. 2008, 67, 909.
a,d), LCK,
a
a
a
25. Hegen, M.; Keith, J. C., Jr.; Collins, M.; Nickerson-Nutter, C. L. Ann. Rhe. Dis.
2008, 67, 1505.