Novel triazolopyridylbenzamides as potent and selective p38α inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.03.099

A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.

Full text of DOI:10.1016/j.bmcl.2012.03.099

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3431–3436
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel triazolopyridylbenzamides as potent and selective p38
a inhibitors
⇑
Josep Aiguadé , Cristina Balagué, Inés Carranco, Francisco Caturla, María Domínguez, Paul Eastwood,
Cristina Esteve, Jacob González, Wenceslao Lumeras , Adelina Orellana, Sara Preciado à, Ramón Roca §,
Laura Vidal, Bernat Vidal
Almirall Research Center, Almirall S.A., Ctra. Laureà Miró 408, E-08980 Sant. Feliu de Llobregat, Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of p38
tallographic data of the initial lead compound cocrystallised with p38
a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis
and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this
a
inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crys-
was crucial in order to uncover
Received 23 February 2012
Revised 23 March 2012
Accepted 28 March 2012
Available online 4 April 2012
a
new class of p38
a
inhibitors and ultimately afforded compounds showing good in vivo efficacy.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
p38
Biaryl-triazolopyridine scaffold
TNF
a Inhibitors
a
LPS-induced endotoxemia
Rat adjuvant-induced arthritis
The p38
cellular serine/threonine (Ser/Thr) kinase that is activated by a
range of environmental stimuli such as TNF
, IL-1b and stress.1,2
In its activated state, p38 phosphorylates a range of intracellular
protein substrates that post-transcriptionally regulate the biosyn-
thesis of TNF and IL-1b. Excessive levels of TNF and IL-1b are
a
mitogen-activated protein (MAP) kinase is an intra-
tolyl amide motif (structure A, Fig. 1) which have been described
in the literature as potent inhibitors of the p38
MAP kinase.14 This
a
a
hinge binding motif generally contains a nitrogen atom embedded
in a fused bicyclic aromatic system which offers a direct interac-
tion with the NH of Met109. At the other end of the biaryl system,
the amide moiety presents two additional interactions with the
corresponding carbonyl and NH units of Glu71 and Asp168, respec-
tively. An additional interaction in the hinge region with the NH of
a
a
a
thought to be responsible for the progression of many inflamma-
tory diseases such as rheumatoid arthritis, psoriasis and inflamma-
tory bowel disease.3–6 The proven ability of p38
a
MAP kinase to
Gly110 amide backbone has been described for several p38a inhib-
efficiently regulate both the release and the activity of such pro-
inflamatory cytokines initially attracted numerous pharmaceutical
companies and independent researchers into pursuing p38a inhib-
itors through a well documented ‘Gly flip’ which may be important
in imparting the high levels of selectivity seen for such com-
pounds.15 The triazolopyridine inhibitor B (Fig. 1)16 is reported to
itors as novel anti-inflammatory drugs.7 However, although initial
preclinical results seemed to be very promising8,9 resulting in the
advancement of several candidates into the clinic,10 recent reports
on clinical trials performed with the most advanced compounds in
rheumatoid arthritis have revealed limited efficacy.11 Currently,
the potential use of such molecules in other indications is under
study.12
have such an interaction with the hinge region of p38a. In an effort
to seek this double interaction in a novel series, a hybrid structure
of A and B was devised (structure C, Fig. 1) and molecule 1 was syn-
thesised as a representative example.17,18
It was satisfying to find that 1 showed good potency in the
enzymatic assay (IC50 = 16 nM) and an X-ray co-crystal of 1 bound
within p38
flip’ was confirmed but, surprisingly, the key interactions between
1 and the hinge region of p38 were established through two
a
was obtained.19 From this study, the presence of a ‘Gly
As part of ongoing efforts toward the discovery of novel p38
a
inhibitors,13 we became interested in biaryl systems based on the
a
molecules of water instead of direct ligand–protein interactions
(Fig. 2). This novel binding mode clearly differs from that seen with
a
inhibitors16 where
⇑
other reported triazolopyridine-based p38
Corresponding author.
E-mail address: josep.aiguade@almirall.com (J. Aiguadé).
Present address: Eli Lilly & Co., Centro de Investigación Lilly, S.A. Avda. de la
Industria, 30 28108 Alcobendas (Madrid) Spain.
direct interactions between the aromatic nitrogens of the triazolo-
pyridine moiety and the amino acids of the hinge region are estab-
lished (vide supra). The rigidity of the biarylamide system together
with the two additional strong interactions of the benzamide
à
Present address: Barcelona Science Park, 08028 Barcelona, Spain.
Present address: Argon Pharma, Barcelona Science Park, 08028 Barcelona, Spain.
§
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.03.099

3432
J. Aiguadé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3431–3436
Asp168
Asp168
O
O
O
N
H
N
H
N
H
A
Glu71
Glu71
O
N
N
N
N
N
R
Met109
Gly110
N
Met109
N
R
F
S
C
1
α
IC50 p38 = 16 nM
F
B
N
N
Met109
Gly110
N
R
Figure 1. Design of triazolopyridylbenzamides C.
Figure 2. X-ray complex of 1 with p38
a
, showing a close-up of the key interactions between the triazolopyridine moiety and the hinge region via two water molecules
(resolution 1.8 Å).
I
I
I
I
subunit with Glu71 and Asp168 increase the distance between the
two nitrogens of the triazolopyridyl core and the hinge region,
allowing for two water molecules to fit in this additional space in
order to establish the observed binding interactions. To the best
of our knowledge, this is the first described example in which
two water molecules are involved in the interaction between a li-
i
ii
iii
HN
HN
N
O
N
HN
N
N
F
N
NH2
N
R
R
2
4
3
O
O
I
X
X
N
H
N
H
gand and the hinge region of the p38a enzyme. As expected for this
iv
type of system, an almost perpendicular arrangement of the aro-
matic rings (torsion angle = 88°) is observed. Additionaly, the
tert-butyl group of 1 lies in a hydrophobic pocket close to the sol-
vent-exposed region.
+
N
N
B
O
O
N
R
N
N
N
R
4
5
6-25
Initial SAR effors were directed towards replacement of the tert-
butyl moiety. Thus, a convergent synthesis was devised in order to
rapidly access molecules containing different substituents at this
position (Scheme 1). Treatment of commercially available 2-flu-
oro-4-iodopyridine with hydrazine hydrate followed by condensa-
tion with different carboxylic acids or acid chlorides afforded the
Scheme 1. Reagents and conditions: (i) Hydrazine hydrate, EtOH, 48 h, rt (90%); (ii)
RCOOH, EDCÁHCl, Et3N, HOBt, ACN or RCOCl, DIPEA, DCM, À78 °C (30–90%); (iii) PS-
PPh3, TMSN3, DEAD (52–90%); (iv) PdCl2dppfÁDCM, Cs2CO3, dioxane, 90 °C, 6 h
(8[R = CF3]–94%).
corresponding hydrazides 3. Cyclization of
supported triphenylphosphine in the presence of TMSN3 and die-
thylazadicarboxylate (DEAD) proceeded smoothly to yield the cor-
3
with polymer
triazolyl moiety (7) provided excellent inhibition in both the bind-
ing assay (IC50: 29 nM) and the hWB assay (IC50: 42 nM). Given this
promising result other compounds possessing other alkyl or cyclo-
alkyl susbtituents at this position were prepared and tested. As
observed in Table 1, most substituents were well tolerated as
ascertained from the binding assay and only the placement of
larger groups such as the tetrahydropyranyl substituent (com-
pounds 15 and 16) resulted in a slight decrease in enzymatic
potency. Substitution at this position with an aromatic ring
resulted in compounds which showed both excellent enzymatic
responding triazolopyridine subunits 4.
A Suzuki-type cross
coupling reaction of compounds of type 4 with boronates of type
5
20 provided the corresponding triazolopyridylbenzamides 6–25.
Biological results are presented in Table 1—both an enzymatic
p38a binding assay as well as a LPS-induced TNFa production as-
say in human whole blood (hWB) were used to test compounds.21
The compound which possessed an isopropyl substituent on the

J. Aiguadé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3431–3436
3433
Table 1
SAR around 3-substituted triazolopyridyl derivatives
O
X
N
H
N
N
N
R
a
a
Compound no.
X
R
p38
a
IC50 (nM)
hWB TNF
a
IC50 (nM)
A (Fig. 1, R = piperidine)
B (Fig. 1, R = t-Bu)
1
6
7
8
—
—
H
F
H
F
—
—
tBu
tBu
iPr
14 1.4
62 16
16 7.2
98 22
143 58
30 2.2
48 4.6
42 23
115 35
b
2
0.9
27 12
0.1
iPr
3
9
H
F
*
*
26 2.6
25 3.5
10
6.7 0.5
213 7.8
11
12
H
F
12 6.9
232 63
*
0.64 0.05
117 31.3
*
*
*
13
14
15
H
F
20 8.2
1.9 0.25
56 19
670 358
550 490
667 50
H
O
O
*
*
16
17
F
30 26
405 106
20 1.7
*
H
6.3 1.8
Cl
*
18
19
20
F
1.6 0.7
38 26
7.2 4.9
305 51
Cl
*
N
N
H
F
Cl
*
0.83 0.02
84
7
Cl
O
21
22
H
F
43 21
1056 342
257 119
*
O
18 0.04
*
23
24
H
F
CF3
CF3
853 184
85 2.5
—
—
O
*
25
F
102 71
1839 (1)
NH2
a
IC50 values represent the mean standard deviation of two or more independent determinations except when indicated otherwise (between brackets).
b
Literature reported binding affinity for compound B: p38a
IC50 = 4.8 nM.16a
as well as hWB activity as observed with compounds 17 and 18. In
the particular case of the chloropyridyl substituent a wider vari-
ability is observed and significant differences are observed be-
tween the benzamide 19 and the meta-fluoro substituted
benzamide 20 in both assays. When this effect of the different sub-
stitution at the meta-position of the benzamide subunit is exam-
ined more thoroughly (H vs F) a clear trend is observed in all the
examples where binding affinity is increased up to one order of
magnitude with fluorine substitution. However, this improved
affinity is not translated into the hWB assay, where, in general,
more erratic results were obtained resulting in apparently illogical
trends. In some instances a one order of magnitude loss in potency
is seen (compounds 9 and 10) whereas in other examples the
potency is maintained (compounds 1 and 6) or even increased
(compounds 17 and 18).22 Measurements of protein plasma bind-
ing (PPB) and permeability for compounds 1 (X = H) and 6 (X = F)
were performed in order to assess whether this might provide an
explanation for the potency difference between both assays (PPB
rat/human (%): 61/58 for 1 and 79/84 for 6; Caco2 (AB/BA) Papp
(10À6 cm/s): 15/18 for 1 and 27/23 for 6). However, data obtained
for both compounds does not account for the potency differences
observed. It is also noticeable that, when stronger electron-with-
drawing groups are placed at this position (compounds 23 and
24) a marked enzymatic potency loss is observed, probably due
to an electronic effect on the triazolopyridyl core by debilitating
the hydrogen bond interaction of the nitrogens to the two water
molecules.
Given that compounds possessing a tert-butyl substituent were
potent in both the binding and hWB assays (compounds 1 and 6)
it was decided to maintain two of the methyl groups of the tert-butyl
substituent and replace the third methyl by more polar substituents
to examine both the tolerance and effects on the biological poten-
cies (Table 2). The placement of a primary amine at this position
(compound 26) resulted in a slight decrease in enzymatic potency

3434
J. Aiguadé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3431–3436
compared to analogue 6. However, enzymatic potency could be
maintained upon introduction of a bulky tertiary amine (NMe2,
Compound 29) at this position. Compound 27 containing an alcohol
in this position also kept enzymatic activity whereas the sulfon-
amide derivative 30 proved to be equipotent to the primary amine
26. When the amine was transformed into the acetamide derivative
28 a 10-fold loss in activity was observed. Unfortunately, all these
substitutions proved to be detrimental in the hWB assay and a sig-
nificant potency drop was generally observed with all compounds.
Only in the case of the compound with the NMe2 substituent 29
was cellular potency somewhat maintained.
F
F
F
F
F
F
F
F
F
i
ii
iii
HN
HN
N
O
N
HN
N
N
N
I
NH2
N
R
R
v
34
32
33
O
X
N
H
v
iv
F
F
F
I
N
36
35
O
X
N
H
i
O
Related to the above compounds, and in order to explore substi-
tution at the triazolopyridyl core, a series of (6,8)-difluorinated
triazolopyridyl derivatives were also prepared by the synthetic
route described in Scheme 2. In an analogous manner to the
previous central core, treatment of commercially available triflu-
oropyridine with hydrazine hydrate followed by condensation with
the corresponding acid or its chloride derivative provided the
hydrazide precursor 33 to the triazolopyridine motif 34. The cycli-
zation step was performed either using POCl3 or polymer supported
triphenylphosphine in the presence of TMSN3 and diethylazadicarb-
oxylate (DEAD) to yield the desired difluorinated central core 34.
Coupling to the upper benzamide part of the molecule could be
accomplished either by reaction of the correponding organozinc
derivative of the triazolopyridyl unit (preparared in situ from the
corresponding lithiated derivative) with the iodobenzamide deri-
vate 35,20 or by a boron-mediated coupling of the iodotriazolopyr-
idyl moiety 38 with the boronate ester of the benzamide unit 5.20
Iodo derivative 38 was prepared by trapping of the afore mentioned
lithited intermediate with iodine or, alternatively, by preparation of
the iodide derivative 36 from trifluoropyridine and subsequent
hydrazide formation and cyclization as depicted in Scheme 2.
Biological results for compounds 39–45 are presented in Table 3.
As before, when compounds were tested against the binding and
whole blood assays, a poor correlation existed. For example,
although very small structural differences exist between com-
pounds 1 and 39, results from the whole blood assay differ by over
an order of magnitude (31 vs 516 nM) whereas in the case of com-
pounds 6 and 4 the difference is only threefold (48 vs 110 nM). It
was also noted that with these difluorinated derivatives the
fluorine atom on the meta position of the benzamide subunit was
pivotal in order to optimize enzymatic activity—compare com-
pound 39 (IC50 = 49 nM) with the fluorinated derivative 40
(IC50 = 6 nM),—and for this reason this fluorine was kept for all the
other derivatives prepared in this series. Again, the tert-butyl group
X
B
N
5
I
I
O
O
H
F
F
F
F
ii + iii
F
F
N
N
HN
N
vi
N
NH2
N
N
R
N
39-45
37
38
R
Scheme 2. Synthetic sequence used to access 6,8-difluorotriazolopyridylbenza-
mides with different substitution at the triazolopyridyl ring. Reagents and
conditions: (i) Hydrazine hydrate, EtOH, 48 h, rt (85%); (ii) RCOOH, EDCÁHCl, Et3N,
HOBt, ACN or RCOOH, HATU, DIEA DMF, or RCOCl, DIPEA, DCM, À78 °C (60–100%);
(iii) POCl3 or PS-PPh3, TMSN3, DEAD (52–90%); (iv) LiHMDS (1 M in hexanes), ZnCl2,
Pd(PPh3)4, (25–58%); (v) LiHMDS (1 M in hexanes), I2, THF (40–53%); (vi)
PdCl2dppfÁDCM, Cs2CO3, dioxane, 90 °C, (25–60%); (vii) LDA, I2, THF (84%).
Table 3
6,8-Difluorotriazolopyridyl derivatives
O
X
N
H
F
F
N
N
N
R
Compound no.
X
R
p38
a
IC50 (nM)a
hWB TNFa
IC50 (nM)a
39
40
41
H
F
tBu
tBu
iPr
49 11
6.2 0.8
6.7 3.7
516 55
116 45
467 225
F
42
F
*
10 4.5
1466 597
N
*
43
F
23 3.5
>5000
Cl
*
44
45
F
F
12 8.1
15 5.1
822 278
124 26
NH2
*
NMe2
Table 2
a
Effect of polar substituents attached to the geminal dimethyl substituent
IC50 values represent the mean standard deviation of two or more indepen-
dent determinations.
O
F
N
H
appeared to be the optimal susbstituent in filling the lipophilic
pocket at the 3-position of the triazolopyridine. Although enzymatic
potency was maintained for compounds with other substituents
such as isopropyl or cyclopropyl (41 and 42), there were inexplica-
ble drops in potency in the functional assay. An aromatic substitu-
ent as well as a polar amino group were also incorporated in the
3-position in order to see the effect and, whilst keeping good bind-
ing affinities, such compounds provided very poor values in the
hWB assay (compounds 43 and 44). Interestingly, replacement of
the NH2 by its dimethylamino derivative led to a significant gain
in potency in the hWB assay whilst maintaining binding affinity
(45 vs 44). Thus, although good binding affinities were obtained
from this difluorotriazolopyridyl derivatives, hWB values were
again completely unpredictable.
N
N
N
R
a
a
Compound no.
R
p38
15.4 4.6
9.4
a
IC50 (nM)
hWB TNFa IC50 (nM)
26
27
28
29
30
31
NH2
177 72
278 156
—
84 10
1110 417
OMe
NHAc
NMe2
NHMs
OH
5
253 90
1.7 0.5
17
2
3.1 1.2
105
2
a
IC50 values represent the mean standard deviation of two or more indepen-
dent determinations.

J. Aiguadé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3431–3436
3435
Table 4
In vitro profiles of selected derivatives
b
c
Compound no.
Rat/Human metabolisma (+NADPH)
Caco-2 (AB/BA) Papp (10À6 cm/s)
Cytotoxicity CHO IC50
(lM)
Rat/Human PPB (%)
1
6
40
<5/<5
<5/<5
<5/6
15/18
27/23
41/25
50% @ 200
107
33% @ 200
l
M
M
61/58
79/84
75/79
l
a
b
c
% turnover after a 30 min incubation period at 37 °C of a 5 lM solution of test compound with hepatic microsomes (1 mg/mL).
Passive permeability through a Caco-2 monolayer determined using 12.5
lM test compound.
For assay details see Ref. 13b.
Table 5
Pharmacokinetic properties of selected derivatives in Wistar ratsa,b
Compound no.
iv (1 mg/kg)
po (10 mg/kg)
AUC (ng h/ml)
t1/2 (h)
AUC (ng h/ml)
Cl (ml/min/kg)
Vss (l/kg)
Cmax
(l
g/ml)
F (%)
1
6
40
3.4
3.8
3.3
2119
2668
8012
7.8
6.5
2.3
2
1.3
0.57
2595
2581
3471
19402
17750
38561
93
66
50
a
Mean values (n = 2).
b
Formulations: iv: 40% PEG + 0.4% HCl 1 N; po: 0.5% methylcellulose + 0.1% Tween 80.
Table 6
Pharmacokinetic properties of selected derivatives in Beagle dogsa
Compound no.
iv (1 mg/kg)
po (1 mg/kg)
t1/2 (h)
AUC (ng h/ml)
Cl (ml/min/kg)
Vss (l/kg)
Cmax (ng/ml)
AUC (ng h/ml)
F (%)
1
6
40
2.5
3.5
7.3
1688
2767
6438
9.9
6.2
2.7
1.7
1.6
1.6
215
—
185
1262
—
5055
75
—
79
a
Mean values (n = 2).
Compounds 1, 6 and 40 were chosen for further profiling since
compounds, resulting in an increased half-life of 7.3 h in dog com-
pared with t1/2 = 3.5 and 2.5 h for compounds 6 and 1, respectively.
To assess in vivo pharmacological activity, compounds 1 and 40
were evaluated in an LPS-induced endotoxemia rat model for their
they exhibited the most balanced potencies in the enzymatic and
whole blood assays. The in vitro metabolism in hepatic micro-
somes, permeability in a Caco-2 cell line and cytotoxicity in a Chi-
nese hamster ovarian (CHO) cell line were performed for the
selected compounds and results are shown in Table 4. Additionally,
all three compounds show a moderate ppb value in both rat and
human in vitro assays.
ability to inhibit TNF
dosed orally 1 h prior to LPS administration and the amount of TNF
in plasma was measured 1.5 h later (coinciding with peak TNF pro-
duction). Both compounds potently inhibited the release of TNF
a release. In this model, compounds were
a
a
a
Very low metabolism was observed in both rat and human
microsomes and the Caco-2 permeation studies indicated all three
compounds should not present permeability issues. In terms of
intrinsic toxicity of the compounds, none of them showed signifi-
cant cytotoxicity (Table 4) towards CHO cells. In addition (data
not shown) none of the compounds showed any significant inhibi-
tion of the major human cytochrome isoforms (1A2, 3A4, 2C9,
with ED50’s of 0.26 and 1.36 mg/kg, respectively. In addition, the
efficacy of both compounds in inhibiting the course of rat adju-
vant-induced arthritis was evaluated. In this model, arthritis was in-
duced by the inoculation of complete Freund’s adjuvant in the left
hind paw of the rat. Compounds 1 or 40 were administered daily
(oral administration) during the last 10 days of the protocol. Moni-
toring of right paw volume revealed that both compounds were effi-
cacious at inhibiting paw oedema with an average inhibition of 60%
and 67% at 3 mg/kg, respectively (see also Ref. 24).
2C19, 2D6) at concentrations below 25
also tested in a kinase selectivity panel,23 the most significant find-
ings being the inhibition of c-Raf (IC50 = 3.2 M) for 1, Ret
(IC50 = 2 M) for 40 and c-Raf and Ret for 6 (66% at 10 M—for each
kinase, respectively).
lM. The compounds were
l
In conclusion, a novel class of p38
fied from a structure-based design. The X-Ray co-crystal structure
of compound 1 bound in the p38 enzyme revealed an unprece-
a inhibitors has been identi-
l
l
a
The pharmacokinetic profiles of the three selected analogues
were determined in the rat (Table 5). Compounds 1 and 6 showed
a moderate clearance and also a moderate volume of distribution.
However, compound 40 had a significantly lower clearance and
volume of distribution. As a result all three molecules showed a
half life of approximately 3.5 h. In addition, all three compounds
displayed good oral exposure, bioavailabilities being greater than
50% in all cases.
dented binding mode in which the inhibitor interacts indirectly
with the hinge region of the kinase via a pair of water molecules.
An extensive SAR study around compound 1 led to the discovery
of two compounds (6 and 40) which showed potent inhibition of
TNFa production both in vitro (whole blood assay) and in vivo,
good overall kinase selectivity and excellent pharmacokinetic
properties. Compounds 1 and 40 also demonstrated significant
anti-inflammatory activity in a rat model of arthritis.
The pharmacokinetic profiles in dog were also evaluated for com-
pounds 1, 6 and 40 (see Table 6). The volume of distribution was
moderate and similar for all three compounds (1.6–1.7 l/kg). In line
with the results from the rat pharmacokinetic studies, compound 40
showed a significantly lower clearance compared to the other
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469; For related triazolopyridine scaffolds showing ‘Gly flip’ see also: (b)
McClure, K. F.; Abramov, Y. A.; Laird, E. R.; Barberia, J. T.; Cai, W.; Carty, T. J.;
Cortina, S. R.; Danley, D. E.; Dipesa, A. J.; Donahue, K. M.; Dombroski, M. A.;
Elliot, N. C.; Gabel, C. A.; Han, S.; Hynes, T. R.; LeMotte, P. K.; Mansour, M. N.;
Marr, E. S.; Letavic, M. A.; Pandit, J.; Ripin, D. B.; Sweeney, F. J.; Tan, D.; Tao, Y. J.
Med. Chem. 2005, 48, 5728; (c) McClure, K. F.; Letavic, M. A.; Kalgutkar, A. S.;
Gabel, C. A.; Audoly, L.; Barberia, J. T.; Braganza, J. F.; Carter, D.; Carty, T. J.;
Cortina, S. R.; Dombroski, M. A.; Donahue, K. M.; Elliot, N. C.; Gibbons, C. P.;
Jordan, C. K.; Kuperman, A. V.; Labasi, J. M.; LaLiberte, R. E.; McCoy, J. M.;
Naiman, B. M.; Nelson, K. L.; Nguyen, H. T.; Peese, K. M.; Sweeney, F. J.; Taylor,
T. J.; Trebino, C. E.; Abramov, Y. A.; Laird, E. R.; Volberg, W. A.; Zhou, J.; Bach, J.;
Lombardo, F. Bioorg. Med. Chem. Lett. 2006, 16, 4339.
9. Haddad, J. J. Curr. Opin. Investig. Drugs 2001, 1070, 2.
10. Dominguez, C.; Powers, D. A.; Tamayo, N. Curr. Opin. Drug Disc. Dev. 2005, 8, 421.
11. Goldstein, D. M.; Kuglstatter, A.; Lou, Y.; Soth, M. J. J. Med. Chem. 2010, 53, 2345.
12. Fischer, S.; Koeberle, S. C.; Laufer, S. A. Expert Opin. Ther. Patents 1843, 2011, 21.
and references cited therein.
17. Compounds in this manuscript were first described in the Almirall patent
application: Vidal, B.; Eastwood, P.; González, J.; Esteve, C.; PCT Int. Appl.
WO2008107125, 2008.
13. (a) Lumeras, W.; Caturla, F.; Vidal, L.; Esteve, C.; Balagué, C.; Orellana, A.;
Domínguez, M.; Roca, R.; Huerta, J. M.; Godessart, N.; Vidal, B. J. Med. Chem.
2009, 52, 5531; (b) Eastwood, P.; González, J.; Gómez, E.; Vidal, B.; Caturla, F.;
Roca, R.; Balagué, C.; Orellana, A.; Domínguez, M. Bioorg. Med. Chem. Lett. 2011,
21, 4310; (c) Eastwood, P.; González, J.; Gómez, E.; Caturla, F.; Balagué, C.;
Orellana, A.; Domínguez, M. Bioorg. Med. Chem. Lett. 2011, 21, 5270; (d)
Eastwood, P.; González, J.; Gómez, E.; Caturla, F.; Aguilar, N.; Mir, M.; Aiguadé,
J.; Matassa, V.; Balagué, C.; Orellana, A.; Domínguez, M. Bioorg. Med. Chem. Lett.
2011, 21, 6253; (e) Lumeras, W.; Vidal, L.; Vidal, B.; Balagué, C.; Orellana, A.;
Maldonado, M.; Domínguez, M.; Segarra, V.; Caturla, F. J. Med. Chem. 2011, 54,
7899.
14. The specific example shown (structure A) is described in: Baldwin, I.;
Bamborough, P.; Haslam, C. G.; Hunjan, S. S.; Longstaff, T.; Mooney, C. J.;
Patel, S.; Quinn, J.; Somers, D. O. Bioorg. Med. Chem. Lett. 2008, 18, 5285.
15. For further discussion on the ‘flip’ binding mode of unrelated series see: (a)
Fitzgerald, C. E.; Patel, S. B.; Becker, J. W.; Cameron, P. M.; Zaller, D.; Pikounis, V.
B.; O’Keefe, S. J.; Scapin, G. Nat. Struct. Biol. 2003, 10, 764; (b) Natarajan, S. R.;
Heller, S. T.; Nam, K.; Singh, S. B.; Scapin, G.; Patel, S.; Thompson, J. E.;
Fitzgerald, C. E.; O’Keefe, S. J. Bioorg. Med. Chem. Lett. 2006, 16, 5809.
16. (a) Jerome, K. D.; Rucker, P. V.; Xing, L.; Shieh, H. S.; Baldus, J. E.; Selness, S. R.;
Letavic, M. A.; Braganza, J. F.; McClure, K. F. Bioorg. Med. Chem. Lett. 2010, 20,
18. During the course of this work a patent application resulting from an
independent study describing triazolopyridylbenzamides as p38
a inhibitors
was published: see WO2008045393, 2008.
19. Coordinates and structure factors for the complex of p38
a with 1 have been
deposited in the RCSB Protein Data Bank (RSCB id code-rscb065714; PDB id
code-3S3I).
20. Syntheses of boronate 5 and iodobenzamide 35 are described in Ref. 17.
21. Full details of all biological assays used in this article can be found in Refs.
13a,e.
22. Although compounds 17 and 18 were the most promising in the series in terms
of potency, they were discarded as they delivered several adducts in the GSH
assay (4% and 10%, respectively).
23. Compounds were tested against a panel of 55 kinases: Compounds were
assayed at Upstate Ltd at single inhibitor concentrations of 10 lM in duplicate
using ATP concentrations corresponding to the Km values of the appropriate
kinases.
24. For full details of in vivo experiments performed on compounds 1 and 40 see:
Balagué C.; Pont, M.; Prats, N.; Godessart, N. Br. J. Pharmacol. 2012, 165 (Epub
ahead of print).