Discovery and characterization of the N-phenyl-N′-naphthylurea class of p38 kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.03.104

An effort aimed at exploring structural diversity in the N-pyrazole-N′-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N′-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-α production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency.

Full text of DOI:10.1016/j.bmcl.2009.03.104

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2386–2391
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and characterization of the N-phenyl-N0-naphthylurea class of p38
kinase inhibitors
Pier F. Cirillo a, Eugene R. Hickey a, Neil Moss a, , Steffen Breitfelder a,b, Raj Betageri a, Tazmeen Fadra a,
*
Faith Gaenzler a, Thomas Gilmore a, Daniel R. Goldberg a, Victor Kamhi a, Thomas Kirrane a, Rachel R. Kroe a,
Jeffrey Madwed a, Monica Moriak a, Matthew Netherton a, Christopher A. Pargellis a, Usha R. Patel a,
Kevin C. Qian a, Rajiv Sharma a, Sanxing Sun a, Alan Swinamer a, Carol Torcellini a, Hidenori Takahashi a,
Michele Tsang a, Zhaoming Xiong a
a Departments of Medicinal Chemistry, Immunology and Inflammation, Cardiovascular Disease, Biologics and Biomolecular Sciences, or Drug Discovery Support, Boehringer
Ingelheim Pharmaceutical, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA
b Department of Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH and Co. KG, Birkendorfer Strasse 65, D-88397 Biberach an der Riss, Germany
a r t i c l e i n f o
a b s t r a c t
An effort aimed at exploring structural diversity in the N-pyrazole-N0-naphthylurea class of p38 kinase
inhibitors led to the synthesis and characterization of N-phenyl-N0-naphthylureas. Examples of these
Article history:
Received 3 February 2009
Revised 20 March 2009
Accepted 23 March 2009
Available online 26 March 2009
compounds displayed excellent inhibition of TNF-a production in vitro, as well as efficacy in a mouse
model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a
sulfonamide functionality in defining inhibitor potency.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
p38 MAP kinase
Inhibitor
Elevated levels of pro-inflammatory cytokines, most notably tu-
mor necrosis factor- (TNF- ) and interleukin-1b (IL-1b), are asso-
ciated with a number of inflammatory diseases.1 Biologics directed
at TNF- and IL-1b, have been approved and marketed for diseases
such as rheumatoid arthritis.2
The p38 mitogen activated protein kinase (p38 hereafter)
plays a central role in the signal transduction pathway leading to
movement of the side chain of Phe 169 on the kinase activation
loop (‘Phe out’ mode).5
a
a
In an effort to expand the structural diversity of this class of
inhibitors, we investigated modifications on the side of the urea
associated with the ‘Phe out’ binding mode. Since the pyrazole
nitrogen atom does not appear to hydrogen bond to the enzyme,
we hypothesized that this heterocyclic ring acts primarily as a scaf-
fold to orient the appended pharmacophores, and that it could be
replaced by a six-membered aromatic ring. We therefore investi-
gated N-phenyl-N0-naphthylurea inhibitors of p38.7
We prepared compounds 5 and 6 as the first examples (Table 1)
for comparison to the methyl pyrazole analogues 3 and 4 and the
more potent tolyl pyrazole analogues 1 and 2. Because of the
intrinsic high affinity and slow binding kinetics of members of this
class of compounds to p38, we relied on a thermal denaturation as-
say as a means of assessing relative binding affinity.8 The higher
the denaturation temperature (Tm) of the enzyme-inhibitor com-
plex, the tighter the binding of the inhibitor to the enzyme. The
Tm values for compounds 5 and 6 were comparable though some-
what lower than the pyrazole analogues 3 and 4, and as expected
were substantially lower than the more elaborated pyrazole ana-
logues 1 and 2. Interestingly, we observed a greater difference in
cell potency between compounds 5 and 6 than we observed be-
tween compounds 1 and 2 or 3 and 4. Compound 6 proved essen-
tially equipotent to compound 2 in the THP-1 and whole blood cell
a
a
the production of a variety of cytokines, including TNF-
a and IL-
1b.3 Therefore intense research has been devoted to the discovery
of p38 inhibitors, as these would be anticipated to have similar
therapeutic benefit to the anti-cytokine biologics, with the conve-
nience of oral dosage, and lower cost.4
We previously described the discovery of the N-N0-diarylurea
inhibitors of p38, which culminated in the clinical compound BIRB
796 (doramapimod; 1).5 We subsequently reported further elabo-
ration of this class of compounds by modifications in the ade-
nine/ATP binding site, as exemplified by compound 2 (Fig. 1).6
The binding mode of these diarylureas to p38 has been de-
scribed. Figure 2 graphically summarizes the key interactions using
compound 2 as an example. The pyrazole tert-butyl substituent
takes advantage of a lipophilic binding site made available by
* Corresponding author. Tel.: +1 203 798 5101; fax: +1 203 791 6072.
E-mail address: nmoss@rdg.boehringer-ingelheim.com (N. Moss).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.104

P. F. Cirillo et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2386–2391
2387
N
N
O
O
O
N
O
O
N
N
N
H
N
H
N
N
H
N
H
N
1
2
BIRB 796
(Doramapimod)
Figure 1. Structures of N-pyrazole-N0-naphthylurea inhibitors of p38.
assays despite having a 9° lower Tm.9 This result was even more
incongruous considering that the relatively weak cell potencies ob-
served for compound 5 fell in line with expectations based on its
Tm value. Intrigued by this result with compound 6, we made other
phenyl analogs with naphthylurea B, focusing initially on changes
at the methyl and tert-butyl positions (Table 2).
O
Lipophilic
(Phe169)
pocket
Phe169
N
Asp168
NH
N
O
Adenine
binding site
N
N
H
N
H
N
CO2-
Lipophilic
(kinase specificity)
pocket
Table 2
Glu71
Effect of substitutions on N-phenyl group
N
Figure 2. Graphical representation of key interactions between 2 and p38.
O
N
O
R
N
H
N
H
Table 1
Effect of changes on the N-aryl portion of the N-aryl-N0-naphthylurea
Compound
R
Tm (°C)
THP-1b IC50 (nM)
HWBc IC50 (nM)
a
N
N
O
O
R
O
N
O
O
R
N
H
N
H
N
H
N
H
6
54.6
9.4
180
A
B
Compound
R
Tm (°C) THP-1b IC50 (nM) HWBc IC50 (nM)
a
7
56.6
29
350
N
N
1
A
63.7
18
780
N
N
8
53.9
57.9
52.3
8.8 (2)
700
2
3
B
A
63.6
54.5
8.0
140
220
10,000
N
N
9
5.5
140
4
5
6
B
A
B
57.9
52.7
54.6
29
380
9.4
230
>10,000
180
O
a
Denaturation temperature of the unphosphorylated human p38:inhibitor
10
76
Not tested
complex; standard deviation for n > 2 experiments typically 0.1–0.5 °C.
b
Values are means of 2–4 experiments, standard deviations for n > 2 experi-
ments typically 50% of reported value.
c
Values are geometric means from 4–12 donor experiments, standard deviation
a,b,cSee notes from Table 1.
typically 50% of reported value.

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P. F. Cirillo et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2386–2391
Table 3
To determine whether the increased potency associated with
Effect of 6-position substituents
the tolyl group over the methyl group in pyrazole-based inhibitors
would translate to the new phenyl-based inhibitors, we prepared
compound 7. We selected a methyl pyrimidine over a tolyl group
since the methyl pyrimidine had previously been identified in
the pyrazole series as an equipotent but less lipophilic tolyl
replacement.6 Compound 7 did have a modestly higher Tm than
compound 6, but its cell potency was more in line with what might
have been predicted based on the Tm-THP-1 trends for compounds
1-5.
Confirmation that the favorable THP-1 cell potency observed for
compound 6 was not a unique occurrence came from the compara-
ble cell potencies obtained for structurally related analogues 8 and
9. A comparison of compound 6 and 10 confirmed that the three
methyls of the tert-butyl group are still required for potency, con-
sistent with what we observed for the pyrazole-based inhibitors.
Since the methoxy derivative 9 provided the best combination of
Tm and cell potency, we selected it as a frame of reference for fur-
ther SAR.
N
4
O
N
O
6
R
N
H
N
H
2
1
O
Compound
R
Tm (°C)
THP-1b IC50 (nM)
5.5
HWBc IC50 (nM)
140
a
9
H-
57.9
11
12
61.5
63.6
5.0
22
H2N
O
9.0
35
N
H
O
O
O
13
14
15
58.7
58.1
56.7
5.1
8.5
12
71
N
H
Compound 9 did not possess ideal physicochemical properties
(pH 7.4 aqueous solubility <0.5 lg/mL). Consequently, in addition
to exploring the SAR of these new phenyl-based inhibitors, we also
wanted to identify opportunities to improve their physicochemical
properties. A single crystal X-ray diffraction of compound 9-
unphosphorylated human p38 complex revealed that the 6-posi-
tion on the phenyl ring is exposed to solvent. Therefore, we ex-
plored simple polar functionality at this position with the initial
intention of establishing if substitutions would be tolerated at this
position (selected examples shown in Table 3).
Unexpectedly the modifications shown in Table 3 had a far
greater effect on Tm than they did on inhibitor aqueous solubility
which was marginally improved at best versus compound 9. Sev-
eral R groups improved Tm 5–7 °C. Intriguingly, the series of com-
pounds in Table 3 displayed a wide range of Tms ranging ꢀ9 °C
from lowest to highest. In contrast, potency in the THP-1 cell and
whole blood assays remained essentially invariant.
110
110
O
N
H
H2N
O
N
H
16
17
64.9
63.3
15
10
120
46
N
O
O
S
N
H
H2N
Despite the apparent Tm-THP-1 assay disconnects, compound
17 emerged as having the best combination of improved whole
blood potency over compounds 1 and 2 together with hydrolytic
stability in vivo that avoided formation of aniline 11. Compound
17 was profiled in a mouse model of lipopolysaccharide-induced
endotoxemia. An oral dose of 3 mg/kg resulted in 57% inhibition
18
19
20
65.5
65.6
56.2
9.4
10
12
74
97
97
O
H
N
O
O
of TNFa production. BIRB 796 (1) did not show significant efficacy
N
at this dose.10
While we had successfully identified phenyl-based p38 inhibi-
tors surpassing our best pyrazole-based inhibitors, we were left
pondering the apparent disconnects between the Tm and THP-1 cell
assay results. Compound 6 and close analogues have relatively low
Tm values but good cell potency while derivatives in Table 3 can
have substantially higher Tm values with little impact on cell po-
tency. Of course one should not always expect good correlations
between molecular and cellular potency based on the impact of
molecular structure on a compound’s ability to reach efficacious
concentrations inside a cell. However, we had seen reasonable
Tm-THP-1 correlations within the pyrazole series. In addition, the
physicochemical properties of the new phenyl based inhibitors
were not substantially different from those of the pyrazole series.
It is conceivable that the thermodynamics of binding to p38 for
phenyl-based inhibitors differs significantly from pyrazole-based
inhibitors. This could impact the relationship between Tm and Kd
enough to make inter-series Tm comparisons less meaningful. This
thermodynamic argument could also apply to inhibitors within a
series, especially if structural modifications create new or different
interactions with p38. This argument could explain the lack of im-
pact of increasing Tm on cell potency for the various compounds in
Table 3. In addition, reaching the limit of differentiation in the
a,b,cSee notes from Table 1.
THP-1 cell assay could be another possible explanation for this dis-
connect. We have never observed an IC50 below 5 nM in this assay
with ours or competitor’s compounds.
Given these Tm–THP-1 assay disconnects, we became particu-
larly interested in verifying whether the presence of a sulfonamide
group truly improves binding affinity (compound 9 versus 17),
since the phenyl sulfonamide portion of 17 became a key piece
in subsequent inhibitor series.11 This was not straightforward to
test.
We attempted to calculate dissociation constants for com-
pounds 9 and 17 using exchange curve binding kinetic analyses.
We previously used this method to generate a Kd for compound
1 (0.1 nM).12 However, the inherent long off rates of our potent
‘Phe out’ p38 inhibitors often impeded accurate off rate extrapola-
tion. This undermined the general utility of this method for deter-
mining Kd values (the half life for dissociation of compound 1 from
p38 was on the order of 24 h). Nevertheless, compound 9 returned

P. F. Cirillo et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2386–2391
2389
Table 4
a Kd value of 1.8 nM, approximately 10-fold weaker than 1 and
consistent with their relative Tms. Unfortunately we could not
generate a reliable Kd for compound 17 due to an inability to
accurately extrapolate its off rate. However, the experiment at
least suggested that compound 17 bound tighter to p38 than
compound 9.
The effect of sulfonamide group on truncated inhibitors
O
O
X
R
N
H
The intrinsic high affinity and slow binding kinetics of these
‘Phe out’ inhibitors also complicated the use of conventional kinase
assays for accurately assessing relative potency. The low concen-
trations of both inhibitor and enzyme required for assessing sub-
nanomolar potency coupled with inherently slow on rates necessi-
tates preincubation times of 24 h or more. Enzyme stability and the
general reproducibility of the assay became issues with this
lengthy preincubation. Since the need for extensive preincubation
diminishes as the potency of the compound decreases, we assessed
the relative potency of three pairs of sulfonamide and non-sulfon-
amide containing compounds lacking the adenine binding site
moiety (Table 4). These truncated analogues were expected to be
significantly less potent such that reliable IC50s could be expected
with a 4 h pre-incubation. Compounds 21 and 22 were the obvious
selections from the N-phenyl-N0-naphthylurea class of p38 inhibi-
tors. We also evaluated two pairs of truncated compounds from
the benzofuran (23 and 24) and benzothiophene (25 and 26) series
previously described.11a Although the truncated benzofuran and
benzothiophene-based inhibitors were inherently weak p38 inhib-
itors, in all three cases the sulfonamide containing inhibitors pro-
R
N
H
N
H
O
O
C
D: X = O
E: X = S
d
a
Compound
R
p38a
IC50 (nM)
Tm (°C)
C
D
E
21
22
23
24
25
26
H-
3900
79
>10,000
4100
>10,000
2700
50.3
56.3
46.2e
48.8
46.9e
51.4
MeSO2NH-
H-
MeSO2NH-
H-
MeSO2NH-
a
See notes from Table 1.
Assay measured inhibition of ATF2 phosphorylation by p38 (LANCE) after 4 h
d
pre-incubation of p38 with inhibitor (value average of two determinations 40%).
e
Result from one test.
duced lower IC50s than the corresponding non-sulfonamide
analogues. These experiments helped support the results of the
Tm assay and substantiated that the sulfonamide group does in-
crease affinity to p38.
An X-ray co-crystal structure of compound 17 bound to unphos-
phorylated human p38 revealed interactions that could help ex-
plain the role of the sulfonamide group (Fig. 3).13 The
sulfonamide methyl group situates itself into a small lipophilic
pocket below the plane of the phenyl ring. In addition, the sulfon-
amide oxygens partake in water mediated hydrogen bonding inter-
actions with Glu 328 and Arg 70 side chains.
The synthesis of the naphthylamine portion of the inhibitors
contained in this paper has been described previously.5,6 The
substituted anilines required to prepare 6, 9 and 10 are commer-
cially available. The synthesis of the sulfonamide containing tert-
butyl aniline in compound 17 has been detailed previously starting
from commercially available 4-tert-butyl-2,6-dinitroanisole.11a The
syntheses of anilines contained in compounds 7, 8, and 19 are
Figure 3. Single crystal X-ray diffraction analysis of the compound 17- unphos-
phorylated human p38 complex, at 2.4 Å resolution, highlighting the interactions of
the sulfonamide group with water bound at the surface of the enzyme.13
a
b
c
d,e
N
O
O
PF6
N+
-
N
O
N
OH
O
N
N
N
O
N
O
H
N
2
N
N
H
NH2
Naphthylamine F
H
7
f
N
N
N
N
Scheme 1. Reagents and conditions: (a) LiOHꢁH2O, MeOH–H2O, rt; (b) POCl3, DMF, 0–110 °C, then NaPF6; (c) CH3C(NH)NH2ꢁHCl, NaOEt, EtOH, reflux; (d) NO2BF4, CH3CN, 0 °C;
(e) HCO2NH4, Pd/C, EtOH, reflux; (f) COCl2, satd aq NaHCO3, CH2Cl2, 0 °C; then naphthylamine F, THF, rt.

2390
P. F. Cirillo et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2386–2391
c
d
a,b
O
O
H
H
HO
N+
O
N+
O
O
OH
O
O
O
O
e
f
H
N
H
N
19
O
N+
NH2
O
O
O
O
O
Scheme 3. Reagents and conditions: (a) NO2BF4, CH3CN, ꢂ35 °C to rt; (b) MeI, K2CO3, DMF, rt; (c) Jones’ reagent, (CH3)2CO, rt; (d) EDC, MeNH2, CH3CN, rt; (e) Cyclohexene, Pd/
C, CH3CN, reflux; (f) COCl2, satd aq NaHCO3, CH2Cl2, 0 °C; then naphthylamine F, THF, rt.
L.; Young, P. R. Nature 1994, 372, 739; (b) Kumar, S.; Boehm, J.; Lee, J. C. Nat. Rev.
Drug Disc. 2003, 2, 717; (c) Ono, K.; Han, J. Cell Signal. 2000, 12, 1.
4. (a) Wagner, G.; Laufer, S. Med. Res. Rev. 2006, 26, 1; (b) Dominguez, C.; Powers,
D. A.; Tamayo, N. Curr. Opin. Drug Disc. Dev. 2005, 8, 421; (c) Nikas, S. N.; Drosos,
A. A. A. Curr. Opin. Invest. Drugs 2004, 5, 1205; (d) Jackson, P. F.; Bullington, J. L.
L. Curr. Top. Med. Chem. 2002, 2, 1011; (e) Cirillo, P. F.; Pargellis, C.; Regan, J.
Curr. Top. Med. Chem. 2002, 2, 1021.
a
b
c
+ O
N
O
NH2
5. (a) Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.; Hickey, E. R.;
Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C. A.; Pav, S.; Proto, A.;
Swinamer, A.; Tong, L.; Torcellini, C. J. Med. Chem. 2002, 45, 2994; (b) Regan, J.;
Capolino, A.; Cirillo, P. F.; Gilmore, T.; Graham, A. G.; Hickey, E.; Kroe, R. R.;
Madwed, J.; Moriak, M.; Nelson, R.; Pargellis, C. A.; Swinamer, A.; Torcellini, C.;
Tsang, M.; Moss, N. J. Med. Chem. 2003, 46, 4676.
N
O
N
d
6. Moss, N.; Breitfelder, S.; Betageri, R.; Cirillo, P. F.; Fadra, T.; Hickey, E. R.;
Kirrane, T.; Kroe, R. R.; Madwed, J.; Nelson, R. M.; Pargellis, C. A.; Qian, K.
C.; Regan, J.; Swinamer, A.; Torcellini, C. Bioorg. Med. Chem. Lett. 2007, 17,
4242.
O
N
H
N
H
NH2
8
7. While these studies were on-going, reports appeared describing N,N0-
diphenylureas as kinase inhibitors, including p38. An N,N0-diphenylurea BAY
43-9006 has successfully been developed into an anticancer drug inhibiting
Raf, VEGFR and PDGFR kinases. See: Lowinger, T. B.; Riedl, B.; Dumas, J.; Smith,
R. A. Curr. Pharm. Des. 2002, 8, 2269.
Scheme 2. Reagents and conditions: (a) HCO2NH4, Pd/C, CH3CN, reflux; (b) NO2BF4,
CH3CN, ꢂ35–0 °C; (c) HCO2NH4, Pd/C, MeOH, reflux; (d) COCl2, satd aq NaHCO3,
CH2Cl2, 0 °C; then naphthylamine F, THF, rt.
8. For an explanation of the binding potency as measured via Tm see: Kroe, R. R.;
Regan, J.; Proto, A.; Peet, G. W.; Roy, T.; Dickert, L.; Fuschetto, N.; Pargellis, C. A.;
Ingraham, R. H. J. Med. Chem. 2003, 46, 4669.
9. Experimental details for the cell assays of LPS-induced TNF production can be
found in Ref. 5.
exemplified in Schemes 1–3, respectively.13 The anilines contained
in compounds 12 to 15 were derived from 4-tert-butyl-2,6-diami-
noanisole11a by treatment with either 1 equiv of the appropriate
acyl chloride, isocyanate or chloroformate. Aniline intermediates
were typically incorporated into the final compound by treatment
with phosgene to form the isocyanate, followed by reaction with
naphthylamine F. The synthesis of compounds 22, 24, and 26 have
been detailed11a and the corresponding des-sulfonamide analogs
21, 23, and 25 were prepared in an analogous manner.
10. Compound 17 showed negligible inhibition of the following kinases when
tested at or above 3 lg/mL: BTK, CDK1, CK1 & 2, DYRK1A, ERK, GSK3b, HGFR,
IGF1R, IKK, IR, JAK3, JNK1A1, LCK, MAPKAPK1B & 2, MKK1, NIK, PDK1, PHK,
PI3K, PKA, PKCa, PRAK, PTK2, ROCK II, RSK2, S6K1, SGK, SYK, TXK. The flowing
table lists kinases showing measurable inhibition:
Kinase
IC50 (lM)
Abl
0.48
7.2
In summary, we identified a class of N-phenyl-N0-naphthylurea
based inhibitors of p38 in which the tolyl pyrazole portion of our
previous series has been replaced by substituted phenyl deriva-
tives. The highlighted compound 17 containing a sulfonamide
group provided potent in vitro and in vivo inhibition of TNF-a pro-
duction. In addition we provided some perspective on the role that
b-Raf
c-Raf
CSK
0.88
62 @ 3*
5.2
ECK
EGFR
FGFR
HEK
5.4
7.7
3.2
jnk2
Lyn
a
2
0.003**
2.4
the sulfonamide group plays in defining inhibitor potency.
VEGFR
PKB /Akt1
3.0
6.4
Acknowledgement
a
pp60src
8.2
The authors thank Rolf Göggel for determining the IC50s for
compounds 21 to 26.
*
Data shown as percent inhibition of p38 at concentration in uM.
**
Value determined by exchange curve binding kinetic analyses.12
References and notes
1. (a) Bradley, J. R. J. Pathol. 2008, 214, 149; Dinarello, C. A. Curr. Opin. Immunol.
1991, 3, 941; (b) Braddock, M.; Quinn, A. Nat. Rev. Drug Disc. 2004, 3, 330.
2. (a) Klinkhoff, A. Drugs 2004, 64, 1267; (b) Barry, J.; Kirby, B. Expert Opin. Biol.
Ther. 2004, 4, 975.
3. (a) Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.; Green, D.;
McNulty, D.; Blumenthal, M. J.; Heys, J. R.; Landvatter, S. W.; Strickler, J. E.;
McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi, G. P.; White, J. R.; Adams, J.
11. (a) Goldberg, D. R.; Hao, M.-H.; Qian, K. C.; Swinamer, A. D.; Gao, D. A.; Xiong,
Z.; Sarko, C.; Berry, A.; Lord, J.; Magolda, R. L.; Fadra, T.; Kroe, R. R.; Kukulka, A.;
Madwed, J. B.; Martin, L.; Pargellis, C.; Skow, D.; Song, J. J.; Tan, Z.; Torcellini, C.
A.; Zimmitti, C. S.; Yee, N. K.; Moss, N. J. Med. Chem. 2007, 50, 4016; (b) Cogan,
D. A.; Aungst, R.; Breinlinger, E. C.; Fadra, T.; Goldberg, D. R.; Hao, M. H.; Kroe,
R.; Moss, N.; Pargellis, C.; Qian, K. C.; Swinamer, A. Bioorg. Med. Chem. Lett.
2008, 18, 3251.

P. F. Cirillo et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2386–2391
2391
12. Pargellis, C. A.; Tong, L.; Churchill, L.; Cirillo, P.; Gilmore, T.; Graham, A. G.;
Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S.; Regan, J. Nat. Struct. Biol. 2002, 9,
268.
13. The coordinates of compound 17 bound to p38 have been deposited with
the RCSB Protein Data Bank (RCSB ID code rcsb051887 and PDB ID code
3GI3).
13. Certain experimental details can be found in: (a) Breitfelder, S.; Cirillo, P. F.;
Regan, J. R. WO02/083642, 2002. (b) Cirillo, P. F.; Kamhi, V.; Regan, J. R.; Tsang,
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