3602
L. Revesz et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3601–3605
R2
increases potency by interacting with the acidic Asp168
F
of p38a.13 The 1,1-dimethylpropynol derivative 6c was
seven times weaker than its NH2-analogue 6b. Satura-
tion of the triple bonds in 6a and 6c led to the 1,1-
dimethylpropylamine 7a and 1,1-dimethylpropanol 7b
with three freely rotatable C–C bonds. The effect of
increased flexibility in the side chain resulted in an 8-fold
loss in potency, with the amine 7a still being three times
more potent than the alcohol 7b. Benzophenones and
benzoylpyridines showed similar SAR; benzophenones
were slightly more potent, when comparing 5a and 6a
with 9a and 10a. 1,1-Dimethylpropynylamine substi-
tuted benzophenones 10a and 10b showed IC50s of 6 and
14 nM, close to the benzoylpyridine analogues 6a,b.
Saturation of the triple bond of 10b to 11 resulted in an
8-fold loss in activity. Introduction of the 1-methyl-4-
hydroxy-4-vinylpiperidine group yielded the highly po-
tent p38a inhibitor 12 (IC50 ¼ 1 nM). Reduction of the
double bond in 12 produced 13 with increased flexibility
of the side chain and an expected (50-fold) loss in
affinity.
Br
Br
a)
b)
R1
+
N
N
H
N
Br
O
F
1
2
3a-c
R2
R2
R1
R1
c)
F
F
O
HO
N
N
H
N
N
H
F
F
5a: R1=Cl, R2=H
5b: R1=Cl, R2=Br
5c: R1=OMe, R2=Br
4a: R1=Cl, R2=H
4b: R1=Cl, R2=Br
4c: R1=OMe, R2=Br
R3
R3
R1
e)
d)
R1
F
F
O
O
N
N
H
N
N
H
F
F
6a: R1=Cl, R3=NH2
6b: R1=OMe, R3=NH2
6c: R1=OMe, R3=OH
7a: R1=Cl, R3=NH2
7b: R1=OMe, R3=OH
Pyridinoyl substituted benzimidazoles 17a and 17b as
well as the benzoyl substituted benzimidazoles 19a and
19b were strong p38a inhibitors, 19a being the most
potent of the series with IC50 ¼ 0.7 nM. As above,
the benzoyl analogues 19a and 19b were 4–10 times
more potent than their pyridinoyl analogues 17a and
17b.
Scheme 1. (a) Pd(OAc)2, NaOtBu, R-(+)-BINAP, 2,4-difluoroaniline,
1,4-dioxane, reflux 1 h, 57%; (b) )78 °C, nBuLi, (2.2 equiv), 2,6 then
add aldehyde 3a–c; 50–60%; (c) CrO3, H2SO4, acetone, room tem-
perature, 10 min, 48–85%; (d) 6a: PdCl2(PPh3)2, CuI, 1,1-dimethyl-
propynylamine, reflux in Et3N 1 h, 63%. 6b: PdCl2(PPh3)2, CuI,
Cs2CO3, 1,1-dimethylpropynylamine, reflux in DIPEA, 30 min, 84%.
6c: PdCl2(PPh3)2, CuI, 1,1-dimethylpropynol, Et3N, DMF, 100 °C,
1.5 h, 70%. (e) Pd/C, H2, EtOH, 15 min, room temperature, 7a: 45%,
7b: 85%.
Compounds with IC50 < 120 nM against p38a were fur-
ther tested in vivo in the acute LPS induced TNFa
release model in the mouse.14 Unsubstituted
benzophenones (R2 ¼ H) 9a and 9b were orally inactive
(Table 1), possibly due to their high lipophilicity. The
hydrophilicity increasing groups 1,1-dimethylpropynyl-
amine, 1,1-dimethylpropynol and 1-methyl-4-hydroxy-
4-vinylpiperidine conferred potent oral activity in 6a–c,
10a,b and 12, which inhibited TNFa by 50–95% at
20 mg/kg po. Benzimidazoles 17a,b and 19a,b were
equally potent, inhibiting TNFa release by 57–93% at
20 mg/kg po. The saturated analogues 11 and 13 were
devoid of oral efficacy.
propylamine 11. The 4-hydroxy-4-vinylpiperidine
substituted benzophenone 12 was obtained by coupling
bromide 9d with vinylstannane 146 under Stille10 con-
ditions. Hydrogenation of 12 gave 13.
Pyridinoylbenzimidazoles 17a,b (Scheme 3) were pre-
pared from aldehydes 15a,b.6 Combining the latter with
the dilithium anion of 26 provided alcohols 16a,b, which
upon Jones8 or MnO2 oxidation rendered the desired
11
benzimidazoles 17a,b.
From the 10 compounds with oral activity in the acute
LPS/TNFa model,14 nine also showed good efficacy in
the subchronic adjuvant induced arthritis (AIA)15 model
in the rat at a dose of 25 mg/kg b.i.d. po; swelling was
inhibited by 36–70% (Table 2). At this stage, compounds
demonstrating low body weight increase in the AIA
model or inhibition of cytochrome P450 isoenzymes16 or
COX-1 inhibition17 or genotoxicity18 were dropped from
further profiling, leaving three structures for further
investigation in the collagen induced arthritis (CIA)19
model in the rat: 10b, 17a and 17b. While 17a proved
ineffective in CIA, 10b and 17b had ED50s of 9.5 mg/kg
qd and 8.6 mg/kg po qd. The ED50 values compared
favourably with two non-pyridinylimidazoles currently
in clinical trials.20;21
Benzoylbenzimidazoles 19a,b (Scheme 4) were prepared
from aldehydes 15a,b,6 which reacted at )78 °C with
1-bromo-4-lithiobenzene to the expected alcohols. The
11
latter were oxidized with MnO2 to the corresponding
ketones. As Buchwald7 reactions failed using the
unprotected imidazoles, a SEM protecting group was
introduced first. Buchwald reaction of 18a,b with 2,4-
difluoroaniline followed by SEM-deprotection yielded
19a and 19b.
Table 1 summarizes the p38a12 IC50 values and the
% inhibition of LPS induced TNFa release in mice upon
oral administration. Bulky R2 substituents such as
bromine in 5b were not favoured, whereas the rigid 1,1-
dimethylpropynylamino group in 6a and 6b increased
p38a inhibitory potency 5–10 fold to IC50 ¼ 19 and
8 nM. One may speculate that the NH2 group in R2
Pharmacokinetic profiles of 10b and 17b in the rat
showed marked differences in their volumes of distri-
bution (Vss) and the maximal plasma concentrations