Syntheses and structure-activity relationships for some triazolyl p38α MAPK inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.01.034

The design, synthesis and biological evaluation of novel triazolyl p38α MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups wer

Full text of DOI:10.1016/j.bmcl.2014.01.034

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Syntheses and structure–activity relationships for some triazolyl
p38a MAPK inhibitors
a
a
a
a
Jean-Paul G. Seerden a, , Gabriela Leusink-Ionescu , Robin Leguijt , Catherine Saccavini , Edith Gelens ,
⇑
Bas Dros a, Titia Woudenberg-Vrenken b, Grietje Molema b, Jan A. A. M. Kamps b, Richard M. Kellogg a
a Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands
b Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ,
The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The design, synthesis and biological evaluation of novel triazolyl p38a MAPK inhibitors with improved
Received 12 December 2013
Accepted 15 January 2014
Available online xxxx
water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial
cells is described. Water-solubilizing groups were introduced via a ‘click’ reaction of functional azides
with 2-alkynyl imidazoles and isosteric oxazoles to generate two small libraries of 1,4-disubstituted
1,2,3-triazolyl p38
a MAPK inhibitors. Triazoles with low IC50 values and desired physicochemical prop-
Keywords:
p38a MAPK inhibitors
Triazole
COX-2, IL-6
Inflammation
erties were screened for in vitro downregulation of proinflammatory gene expression and were formu-
lated in SAINT-O-Somes. Triazolyl p38
promising in vitro activity.
a
MAPK inhibitor 88 (IC50 = 0.096
lM) displayed the most
Ó 2014 Elsevier Ltd. All rights reserved.
The design and synthesis together with pharmacological and
clinical evaluation of p38 MAPK (mitogen-activated protein ki-
cross-coupling arylations of 2,4,5-tribromoimidazole and cycload-
dition of tosylmethylisocyanide with aldimines.9
a
nase) inhibitors have formed an intense area of research in both
We desired a cost-effective and rapid synthetic method to con-
struct a library of novel pyridinyl imidazoles with improved phys-
icochemical properties that would allow incorporation into
cationic liposomes (SAINT-O-Somes) targeted at diseased endothe-
lial cells.10 The preferred position to modify physicochemical prop-
erties is the imidazole C-2 position.1 As alternative to the
previously described methods powerful cross coupling reactions11
methods may provide the flexibility necessary for construction of
such libraries with complete regioselectivity using a versatile
pyridinyl imidazole building block obtained from simple 1-
methyl-1H-imidazole. Our aim was to replace the 4-methylsulfa-
nylphenyl group in lead compound SB203580 at imidazole C-2
by functionalized 1,4-disubstituted 1,2,3-triazoles obtained by
means of the well-established 1,4-regioselective Cu(I)-catalyzed
1,3-dipolar cycloaddition (‘click’ reaction)12 of azides and alkynes
(CuAAC). As described below this strategy enabled the synthesis
of a library of novel pyridinyl imidazoles with the possibility to im-
prove physicochemical properties by varying the azide substitu-
ents. The general synthetic approach started with the highly
efficient straightforward multigram synthesis of the novel C-2
unsubstituted imidazole 6 and the known isosteric oxazole 1113
scaffolds (Scheme 1).
the pharmaceutical industry and academia. The subject has been
thoroughly reviewed.1 The p38
a
MAP kinase signaling pathway
is responsible for the expression of pro-inflammatory cytokines,
including tumor necrosis factor alpha (TNF- ), interleukine 1-beta
a
(IL-1b), IL-6 and COX-2. These cytokines are elevated or dysregu-
lated in many inflammatory and autoimmune diseases such as
rheumatoid arthritis, osteoarthritis, septic shock, asthma, chronic
obstructive pulmonary disease, inflammatory bowel disease, Cro-
hn’s disease, psoriasis, acute coronary syndrome, multiple sclero-
sis, diabetes mellitus and cancer. The discovery of p38
a MAP
kinase as the target of the widely studied pyridinyl imidazoles,
with SB2035802 as lead compound, has led to a continuing search
for increased specificity and potency as exemplified by structurally
related ATP competitive inhibitors, such as RWJ67657,3 ML 3403,4
JNJ7583979,5 L-7900706 and RPR2034947 (Fig. 1). Despite the po-
tential benefits none of the pyridinyl imidazoles has reached the
clinic yet because of toxicity problems, often related with off-tar-
get selectivity and their highly lipophilic character.8 Synthetic ap-
proaches to this class of compounds have been described starting
from cyclocondensation of ketoamides with amines, reaction 1,2-
dicarbonyl compounds with ammonia and aldehydes, Suzuki
Regioselective Pd-catalyzed direct C-5 arylation14 of 1-methyl-
1H-imidazole 2 with 4-bromopyridine HCl 1 afforded the 4-(1-
methyl-1H-imidazol-5-yl)pyridine 3 in 70% yield. Regioselective
⇑
Corresponding author. Tel.: +31 050 5757386; fax: +31 050 5757399.
E-mail address: j.p.g.seerden@syncom.nl (J.-P. G. Seerden).
http://dx.doi.org/10.1016/j.bmcl.2014.01.034
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
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2
J.-P. G. Seerden et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
F
F
F
O
S
N
N
N
N
N
N
S
OH
H
N
N
N
N
SB203580
RWJ67657
ML 3403
NH
F
F
O
F3C
N
N
O
N
N
N
NH
N
(r)
N
N
H
O
NH2
O
N
N
N
NH
N
NH
N
N
NH
(S)
(S)
JNJ7583979
L-790070
RPR203494
Figure 1. Pyridinyl imidazole type p38
a
MAP kinase inhibitors.
F
F
F
Br
Br
N
N
N
N
B(OH)2
a
b
N
5
c
+
N
N
N
N
N
N
.HCl
N
1
2
3
4
6
F
F
F
F
O
O
N
d
e
f
g
O
O
O
Br
N
Cl
Me
OMe
N
N
N
7
8
9
10
11
Scheme 1. Regioselective synthesis of 6 and 11. Reagents and conditions: (a) Pd(OAc)2, PPh3, K2CO3, DMF, 110 °C, 67 h, 70%; (b) NBS, CH3CN, 93%; (c) Pd(dppf)Cl2, CsF,
BnEt3NCl, toluene, H2O, reflux, 24 h, 90%; (d) N,O-dimethylhydroxylamine HCl, Et3N, CH2Cl2, 100%; (e) LDA, À78 °C, 4-picoline, 1 h, then rt, 18 h, 98%; (f) Br2, AcOH, quant.; (g)
formamide, H2SO4, 15 min 150 °C, microwave, 15%.
imidazole C-4 bromination with NBS gave 4-(4-bromo-1-methyl-
1H-imidazol-5-yl)pyridine 4 in 93% yield. The subsequent Pd(dppf)
Cl2 catalyzed Suzuki reaction of 4 with 4-fluorophenylboronic acid
5 under phase transfer conditions gave 4-(4-(4-fluorophenyl)-1-
methyl-1H-imidazol-5-yl)pyridine 6 in 90% yield. The synthesis
of isosteric oxazole 11 was performed in 15% overall yield from
4-fluorobenzoyl chloride 7 over four steps according to literature
procedures.14 Subsequent C-2 lithiation of 6 or 11 followed by
iodination gave 2-iodoimidazole derivative 12 or 2-iodooxazole
derivative 13 (Scheme 2).
Pd-catalyzed Sonogashira alkynylation of 12 and 13 with 1-tri-
isopropylsilylacetylene afforded the TIPS protected ethynyl imid-
azole 14 and oxazole 15, initially in 16–17% yield on use of
lutidine as solvent and base. The yield of 15 could be increased
to 81% by using Et3N as base in THF solution. Alternatively, a
Ni(cod)2/dppbz (1,2-bis(diphenylphosphino)benzene) catalyzed
direct C-2 alkynylation of 6 or 11 with 2-bromo-1-triisopropylsi-
lyl-acetylene11b afforded the protected alkynes 14 and 15, respec-
tively, in one step. TBAF deprotection of the TIPS group afforded
the key alkyne building blocks 16 and 17 in 79% and 60% yield. A
structurally diverse set of aromatic and aliphatic azides was pur-
chased (19, 21, 25, 28–37) or prepared (23, 24, 26, 27, 38, 39)15
prior for use in the subsequent CuAAC reaction with 16 and 17
to provide novel triazolyl p38a MAPK inhibitors 40–74 (Scheme 3).
The aryl azides 18, 20, 22 were prepared in situ from the corre-
sponding arylboronic acids using a Cu(II)-catalyzed Chan–Lam type
reaction16 and were used without isolation in a two-step one-pot
fashion by addition of Na-ascorbate to promote the subsequent
Cu(I)-catalyzed cycloaddition with alkynes 16 and 17 (Scheme 4).
In general, the conversion of the alkyne and azide in the Cu-cat-
alyzed regioselective 1,3-dipolar cycloaddition was high and was
accelerated by microwave heating (20 min, 100 °C). For example,
triazole 52 was prepared in 65% yield after 20 min heating at
100 °C compared to 20% yield after 6 days at room temperature.
The isolated yields of the triazole cycloadducts 40–74 were moder-
ate to good. Imidazole based triazoles were obtained in higher
yields than the isosteric oxazole based triazoles. Many different
functional groups such as alcohols, amines, and carboxylic acids
F
F
F
F
N
X
N
X
N
X
N
X
a
b
c
I
TIPS
TIPS
N
N
N
N
6 X = NMe
12 X = NMe
13
14 X = NMe
16 X = NMe
11
15
17
X = O
X = O
X = O
Br
X = O
d
TIPS
Scheme 2. Alkynes 16 and 17 via direct C-2 alkynylation. Reagents and conditions: (a) LDA, I2, 93% (12); (b) TIPS-acetylene, Pd(PPh3)4, CuI, lutidine, 17% (14), 16% (15; Et3N,
THF: 81%); (c) TBAF, THF, 79% (16) and 60% (17); (d) Br-acetylene-TIPS, Ni(cod)2, CuI, dppbz, 55% (14), 47% (15).
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J.-P. G. Seerden et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
F
F
R
N
X
N
X
CuSO4.5H2O
Na-ascorbate
EtOH, H2O
N
N
N3
R
+
N
16-95% c.y.
N
N
16
18 39
-
40 74
-
X = NMe
17 X = O
Scheme 3. Synthesis of triazolyl p38
a
MAPK inhibitors 40–74.
F
Cu(II)-catalyzed
NaN3
Cu(OAc)2
MeOH
Cu(I) catalyzed
OH
16 or 17
Ar
B
N
X
N3 Ar
N
N
HO
Ar
Na-ascorbate
water
18, 20, 22
N
N
NMe2
Ar =
40 X= NMe, 41 X = O
44 X= NMe
OMe
47
48
X = O
OH
X= NMe,
O
Scheme 4. Two-step one-pot copper(II)- and copper(I)-catalyzed synthesis of 1,2,3-triazoles from arylboronic acids.
could be used in this reaction without the need for protective
groups.
isosteric isoxazoles but were less active than the lipophilic refer-
ence compounds SB203580 or JNJ7583979.18 No significant p38
a
The inhibition of p38
a
MAP kinase by the first set of triazolyl
MAPK inhibition was observed with lipophilic substituents such
as N,N-dimethylanilines 40 and 41, tetra-O-acetyl-protected 2-glu-
cose 50 and 51, ethyleneglycol ethers 58–62, benzyl 65, ethyl ester
67 and diethyl phosphonate 73. The influence of the position of the
water solubility enhancing substituents R on IC50, LLE and LogS
was further investigated by simple functional group transforma-
pyridinyl imidazoles 40–74 was determined by a radiometric IC50
profiling assay. The IC50 data, the calculated LLE17 (Ligand
Lipophilicity Efficiency) and LogS (water-solubility) values are gi-
ven in Table 1. The results show that the imidazole based triazolyl
compounds displayed stronger p38
a
MAPK inhibition than their
Table 1
Yield, IC50, LLE and LogS of novel triazoles
f
Azide
R
Triazole
c.y.a (%)
IC50
(lM)
LLEg
LogSh
NMe2
40 X = NMe
41 X = O
20
16
1.4
19.5
1.6
0.8
À6.05
À5.62
18
OH
O
42 X = NMe
43 X = O
94
0.14
0.19
2.9
3.1
À5.81
À5.38
19
20
91c
OMe
44 X = NMe
46
0.99
2.1
À5.87
O
45 X = NMe
46 X = O
51c,d
44c,d
1.53
6.51
2.2
2.0
À5.51
À5.08
21
O
OH
47 X = NMe
48 X = O
26d
22d
1.59
2.17
2.2
2.4
À4.71
À4.28
22
23
OH
49 X = O
24
n.d.
n.d.
n.d.
O
O
OH
O
OAc
AcO
AcO
2
50 X = NMe
51 X = O
92
58
>100
>100
n.d.
n.d.
À5.96
À5.53
24
25
26
OAc
O
OH
HO
HO
2
52 X = NMe
53 X = O
65c
30
0.71
1.19
6.2
6.4
À3.95
À3.52
OH
O
OAc
OAc
54 X = NMe
55 X = O
93c
46c
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
AcO
OAc
(continued on next page)
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J.-P. G. Seerden et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 1 (continued)
f
Azide
R
Triazole
c.y.a (%)
IC50
(lM)
LLEg
LogSh
O
O
MeO
56 X = NMe
57 X = O
66c
79c
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
27
AcO
OAc
NH2
OAc
O
O
O
28
29
58 X = NMe
40
5.18
4.2
À2.72
3
OH
3
59 X = NMe
60 X = O
82
83
11.2
12.5
3.9
4.2
À3.74
À3.31
À5.40
À4.97
À4.02
À3.58
OH
7
61 X = NMe
62 X = O
63 X = NMe
64 X = O
58
11.6
23.5
0.14
0.38
5.0
5.0
4.0
4.0
30
31
95
TMS (H)b
66e
33e
32
33
65 X = O
64
30
158
À1.1
À5.68
À3.48
OH
O
66 X = NMe
0.50
4.4
67 X = NMe
68 X = O
75
46
1.87
n.d.
2.8
n.d.
À4.65
34
35
36
n.d.
OEt
O
69 X = NMe
70 X = O
74
43
1.44
11.4
4.6
4.1
À2.96
À2.26
OH
O
71 X = NMe
72 X = NMe
73 X = NMe
33
83
42
1.49
n.d.
1.7
À3.18
n.d.
OH
tBuO
O
37
38
n.d.
n.d.
O
OH
O
P
OEt
OEt
Boc
>100
n.d.
F
39
74 X = NMe
74
n.d.
n.d.
n.d.
N
a
Isolated yields with >98% purity.
b
c
d
e
f
Both azide 31 (R = TMS) and NaN3 gave 63 and 64 (R = H).
Microwave, 20 min, 100 °C.
HCl salt.
Microwave, 20 min, 140 °C, dioxane, NMP.
Radiometric p38
a
MAPK IC50 assay, ProQinase GmbH, Germany.
LLE (Ligand Lipophilicity Efficiency) = pIC50—cLogP.
LogS: calculated water solubility (moles/L) using EPIWEB 4.0 WSKOWWIN v1.41; n.d.: not determined.
g
h
tions of some of the triazolyl cycloadducts 40–74. For example,
carboxylic, phosphate or phosphonate ester saponification (with
LiOH, I2 or TMSBr, respectively) afforded the corresponding carbox-
ylate, phosphate or phosphonate derivatives 76–87 with lowered
IC50 and improved aqueous solubility (Table 2). The 2-hydroxy-
ethyl group in 66 displayed activity similar to that of acetic acid
derivative 80 or phosphate derivative 86 indicating a favorable
hydrogen bond donor/acceptor interaction in the ATP-binding
Introduction of the N-2-hydroxyethyl-piperazine amide as in 91
and 92 increased the IC50 values. Boc-deprotection of 74 afforded
the potent fluoropiperidine HCl salt 88 with IC50 = 96 nM. Intro-
duction of a 3-fluoropiperidine improved the physicochemical
properties and oral bioavailability of selective B-raf kinase inhibi-
tors and 5HT2B antagonists.19 The regioselectivity of the CuAAC
1,3-dipolar cycloaddition of 16 and ethyl 2-azidoacetate 34 was
reversed by using 15 mol % Cp*Ru(PPh3)2Cl as catalyst in refluxing
toluene to afford the corresponding 1,5-disubstituted 1,2,3-tria-
zole20 93, the formal 1,5-regioisomer of 65, in 56% yield. Ester
hydrolysis of 93 with 4 N HCl in dioxane at room temperature
for 4 days followed by conversion to the choline salt and lyophili-
zation gave 94 in 46% c.y. The 1,5-disubstituted 1,2,3-triazoles 93
pocket. Conformational restriction by substituents
a to the carbox-
ylic acid in 69, 70, 71, 72 and 83 lowered the potency. From a
medicinal chemistry point of view the aryl series displayed some
interesting differences. The para- and meta-benzoic acids 42, 43
and 84 were ten times more potent than the ortho-benzoic acids
45 and 46 indicating again a favorable H-bonding interaction in
the kinase ATP pocket. The ortho-phenols 47 and 48 showed simi-
lar poorer IC50 values than the ortho-benzoic acid 46. The pKa of the
triazolyl substituent was further varied by introduction of amino
alcohols and basic amines via HATU-mediated reaction with
carboxylic acids 80 and 84 to provide amides 89, 90, 91, 92 with
increased hydrophilic properties. The 3-hydroxypropylamino- or
and 94 did not exhibit relevant p38a MAPK inhibition.
The IC50 data and the calculated LLE and LogS values were
among the drug-like selection criteria21 for in vitro screening of
seventeen compounds for inhibition of inflammatory gene expres-
sion of TNF-a-activated HUVECs (human umbilical vein endothe-
lial cells) and for lipid based formulation. SB203580, imidazole 6
and fluoropiperidine 88 displayed equipotent in vitro inhibition
2-hydroxyethylamino amides 89 and 90 displayed p38
a
MAPK
of COX-2 and IL-6 gene expression (10
lM). Glucose derivative
inhibition similar to the parent carboxylic acids.
52 showed low in vitro activity. Liposomal formulation of
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J.-P. G. Seerden et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
Table 2
IC50, LLE and LogS of novel p38
a MAPK inhibitors
F
N
R
X
N
Compound
X
R
IC50
(lM)
LLE
LogS
JNJ7583979
SB203580
6
11
0.006
0.040
0.43
4.4
4.6
3.7
3.5
À5.55
À4.34
À3.73
À3.31
NH
NMe
O
PhS(O)Me
H
0.60
16
17
NMe
O
0.73
1.79
2.7
2.7
À4.14
À3.71
75
NMe
0.46
3.8
À3.57
OH
O
OH
OH
76
77
NMe
O
0.40
5.73
6.8
6.1
À3.65
À3.22
N
N
N
N
HO
OH
78
79
NMe
O
0.59
1.17
6.2
6.3
À3.77
À3.34
N
N
O
O
OH
HO
OH
OH
OH
N
N
80
NMe
0.74
6.1
À2.90
O
N
N
O-Li+
81
82
NMe
O
0.43
3.2
8.1
7.6
À1.88
À1.45
N
N
O
O-Na+
O
83
84
85
NMe
NMe
NMe
2.3
5.8
2.8
n.d.
À3.2a
À5.81
n.d.
O
N
N
O-Na+
N
N
N
OH
O
0.185
0.091
N
N
O
N
N
O-
Me3N
O
OH
ONa
P ONa
À4.0a
À1.23
N
N
86
87
NMe
NMe
0.25
0.35
5.5
9.7
O
N
N
NaO ONa
P
N
N
O
F
88
NMe
0.096
7.1
À3.85
N
NH
N
.HCl
N
H
N
OH
89
90
NMe
NMe
0.29
0.89
4.0
5.1
À5.24
À3.12
N
N
O
N
N
H
N
N
N
OH
O
O
N
91
O
2.4
4.6
À4.03
N
OH
N
N
N
(continued on next page)
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J.-P. G. Seerden et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 2 (continued)
Compound
X
R
IC50
3.8
(lM)
LLE
4.6
LogS
OH
N
N
92
93
NMe
À3.45
N
N
O
N
N
N
N
OEt
O
NMe
NMe
56
1.3
À4.65
N
N
N
O
94
4.2
n.d.
n.d.
Me3N
OH
O
a
Water solubility calculated for corresponding carboxylic acid.
SB203580 or JNJ7583979 into SAINT-O-Somes10 failed due to their
high lipophilicity. Formulation of 52 proceeded with 84% retention
after 7 days but after anti-E-selectin antibody coupling no in vitro
activity was observed. Formulation of carboxylic acids 80 (16%
retention) and 84 into SAINT-O-Somes was not effective, whereas
the isosteric water-soluble oxazole 82 gave 67% retention. The
disodium phosphate 86 degraded to alcohol 66 during formulation.
Remote loading of 6 and 88 into SAINT-O-Somes resulted after 7
days in 95% and 92% retention, respectively. Anti-E-selectin anti-
body coupling to these formulated liposomes resulted however
in complete release of 6 whereas 88 partially remained inside
the SAINT-O-Somes.
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In summary, we have applied a reaction sequence of regioselec-
tive direct C–H arylation and cross coupling alkynylation of imida-
zoles and oxazole, followed by azide ‘click’ reactions with complete
regioselective control, to provide access to novel triazolyl p38
a
MAPK inhibitors with improved water solubility for further biolog-
ical evaluation and drug delivery studies.22 We believe that the
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Acknowledgments
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This work was sponsored by the Top Institute Pharma (TI Phar-
ma project D5-301, The Netherlands). The authors gratefully
acknowledge the discussions with Eduard Talman and Marcel Ruit-
ers (Synvolux Therapeutics, Groningen, The Netherlands).
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Supplementary data
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Supplementary data associated with this article can be found, in
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034. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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Please cite this article in press as: Seerden, J.-P. G.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.01.034