Trimethylsilylpyrazoles as novel inhibitors of p38 MAP kinase: A new use of silicon bioisosteres in medicinal chemistry

Article abstract of DOI:10.1016/j.bmcl.2006.10.044

The synthesis, physicochemical properties and pharmacological profiles of two novel silicon-containing p38 MAP kinase inhibitors are described.

Full text of DOI:10.1016/j.bmcl.2006.10.044

Bioorganic & Medicinal Chemistry Letters 17 (2007) 354–357
Trimethylsilylpyrazoles as novel inhibitors of p38 MAP kinase:
A new use of silicon bioisosteres in medicinal chemistry
Matthew J. Barnes, Richard Conroy, David J. Miller,* John S. Mills, John G. Montana,à
Parminder K. Pooni, Graham A. Showell, Louise M. Walsh and Julie B. H. Warneck
Paradigm Therapeutics Ltd, 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PA, UK
Received 14 September 2006; revised 19 October 2006; accepted 20 October 2006
Available online 24 October 2006
Abstract—The synthesis, physicochemical properties and pharmacological profiles of two novel silicon-containing p38 MAP kinase
inhibitors are described.
Ó 2006 Elsevier Ltd. All rights reserved.
The pharmaceutical industry has an ongoing need for
new and safe medicines with a genuine biomedical
benefit, a clean IP position and commercial viability.
Sila-substitution (C/Si exchange) of existing drugs or
development candidates is one possible approach to
the search for new drug-like entities that have beneficial
biological properties and a clear IP position.1
1), a non-peptidic p38 MAP kinase inhibitor from Boeh-
ringer Ingelheim which recently underwent clinical eval-
uation for the treatment of several inflammatory
diseases, including rheumatoid arthritis, Crohn’s disease
and psoriasis.6
In order to combine scientific data from the literature
with our own remit of using silicon as an isostere for car-
bon in medicinal chemistry, we synthesised compound 2
(the silicon analogue of BIRB-796) and investigated the
in vitro activity, physicochemical and pharmacokinetic
properties of the silicon–carbon pair. A further com-
pound 3, in which the silylated pyrazole unit was re-
placed by an aryl silane, was also investigated (Fig. 1).
Kinases represent an important family of therapeutically
relevant targets for which a marketable compound
appears achievable.2 The p38 mitogen-activated protein
kinase (p38 MAP kinase; SAPK2a) is an intracellular
serine/threonine kinase that can be activated by a range
of environmental stimuli such as stress, or via the im-
mune response. The discovery of novel chemical entities
as potent and selective inhibitors of p38 MAP kinase
and their efficacy in several animal models of inflamma-
tion has validated this enzyme as an important anti-
inflammatory target.3,4
The silicon analogue of BIRB-796 was synthesised
according to the procedure shown below (Scheme 1).
Modification of a known protocol7 for the [3 + 2]
cycloaddition reaction of trimethylsilylacetylene (4) to
ethyl diazoacetate (5) in the absence of solvent led to
the pyrazole 6 in good yield. Use of a known proce-
dure8 for the copper(II)-mediated arylation of pyraz-
oles utilizing para-tolylboronic acid afforded both 7a
(major) and 7b (minor), which were easily separable
by standard column chromatography. Ester 7a was
hydrolysed under basic conditions to afford the corre-
sponding carboxylic acid 8. This acid was then convert-
ed to the isocyanate in situ, which was allowed to react
with the known amine 96 to afford the direct silicon
analogue of BIRB-796 (2) in good overall yield. In or-
der to allow direct comparison within our own assay
systems, BIRB-796 was synthesised according to the lit-
erature procedure.6
Recently, there have been many publications describing
p38 MAP kinase inhibitors which include small hetero-
cyclic rings such as imidazole and pyrazole, placing se-
vere restrictions on the free patent space for such
scaffolds.5 This is typified by BIRB-796 (Doramapimod,
Keywords: Silicon bioisostere; p38 MAP kinase.
*
Corresponding
dmiller@paradigm-therapeutics.com
author.
Tel.:
+44
1223
477910; e-mail:
Present address: AstraZeneca, Mereside, Alderley Park, Macclesfield
SK10 4TG, UK.
à
Present address: Argenta Discovery, 8/9 Spire Green Centre, Flex
Meadow, Harlow CM19 5TR, UK.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.044

M. J. Barnes et al. / Bioorg. Med. Chem. Lett. 17 (2007) 354–357
355
Figure 1. The structures of BIRB-796 and silicon-containing p38 MAP kinase inhibitors.
Scheme 1. The synthetic route to compound 2. IMS, industrial methylated spirits; DPPA, diphenylphosphoryl azide.
X-ray quality crystals of the acid 8 derived from the ma-
jor product of the cyclisation reaction (7a) were ob-
tained. An X-ray structure determination allowed for
the unequivocal assignment of the compound’s struc-
ture, and in particular the regiochemistry around the
pyrazole ring (Fig. 2).9 By association, the regiochemist-
ry of the final compound can be confirmed.
We were intrigued by the potential replacement of the
silylated pyrazole ring with an electron-rich aromatic

356
M. J. Barnes et al. / Bioorg. Med. Chem. Lett. 17 (2007) 354–357
Figure 2. X-ray crystallographic determination of the structure of the acid 8.
carbocycle which, based on literature precedent,10
should also provide a highly potent p38 MAP kinase
inhibitor. Thus, the amine 10 was allowed to react with
phosgene and then the amine 9 in the presence of Hu-
nig’s base to afford the aryl silane 3 in good yield
(Scheme 2).
Table 1. Physicochemical data for compounds 1 and 2
Compound
pKa
logP
logD at pH
1
2
6.0
6.5
7.4
1 (BIRB-796)
2
1.9
2.3
6.4
6.3
5.2
4.7
4.6
4.3
4.9
4.5
5.1
4.7
The physicochemical parameters for the C/Si analogues
1 and 2 have been measured (Table 1).11 These data indi-
cate that the exchange of carbon for silicon has an effect
on both the pKa of the aromatic nitrogen heterocycle
and the overall lipophilicity of the molecule. Whilst it
is common for the lipophilicity of silicon compounds
to be equivalent to or greater than their carbon ana-
logues, we were gratified to see in this instance, the sili-
con compound was moderately less lipophilic than its
carbon counterpart.
Table 2. The in vitro activity of compounds 1–3 against p38 MAP
kinase (human)
Compound
Human p38 MAP kinase IC50/nM
1 (BIRB-796)
55 51 (n = 3)
64 50 (n = 3)
3* (n = 1)
2
3
* In this assay compound 1, IC50 value = 9 nM and compound 2, IC50
value = 7 nM.
The in vitro activities of compounds 1, 2 and 3 in a p38
MAP kinase enzyme assay have been determined (Table
2).12 When the three compounds were tested in parallel
Table 3. The stability of compounds 1, 2 and 3 in human liver
microsomes (percentage turnover after 40 min at 37 °C; 1 lM concen-
tration of compound)
they showed almost equivalent inhibition ( ). Thus sug-
*
Compound
Microsomal % turnover
gesting that neither the introduction of silicon nor the
exchange of the pyrazole for the electron-rich aryl sys-
tem is detrimental to the potency of the compounds.
1 (BIRB-796)
79 (n = 1)
66 (n = 1)
94 (n = 1)
2
3
The stability of compounds 1, 2 and 3 to degradation
by human liver microsomes has also been determined
(Table 3).13 All compounds demonstrated similar resis-
tance to degradation by such species, the silicon switch
compound 2 appearing to be more stable than its carbon
analogue.
These data suggest that the new silicon-derived com-
pound 2 is a potent inhibitor of p38 MAP kinase and is
not substantially degraded by human liver microsomes.
We therefore proceeded to demonstrate good activity in
Scheme 2. The synthetic route to aryl silane 3.

M. J. Barnes et al. / Bioorg. Med. Chem. Lett. 17 (2007) 354–357
357
Table 4. In vivo effect of BIRB-796 and compound 2 on levels of
TNF-a following LPS-challenge
References and notes
1. Bains, W.; Tacke, R. Curr. Opin. Drug. Disc. Dev. 2003, 6,
526; Showell, G. A.; Mills, J. S. Drug Discovery Today
2003, 8, 551.
TNF-a levels (pg/mL)
30 min 120 min
Time post dose
2. For example, see Kumar, S.; Blake, S. M. HEP 2005, 167,
65; Olson, J. M.; Hallahan, A. R. Trends Molec. Chem.
2004, 10, 125; Saklatvala, J. J. Curr. Opin. Pharmacol.
2004, 4, 372.
3. Badger, A. M.; Bradbeer, J. N.; Votta, B.; Lee, J. C.;
Adams, J. L.; Griswold, D. E. J. Pharmacol. Exp. Ther.
1996, 279, 1453.
Vehicle
3546
2950
1 (BIRB-796)
2
Dexamethasone
2083 (À41%)
1443 (À59%)
495 (À86%)
1761 (À40%)
1616 (À45%)
nta
a Not tested.
an in vivo efficacy model. Compounds 1 and 2 were tested
in an LPS (lipopolysaccharide from Escherichia coli
0111:B4)-induced model of TNF-a (tumour necrosis fac-
tor) release in mice alongside 3 mg/kg po dexamethasone
as a positive control. The animals received either vehicle,
or 10 mg/kg po of compounds 1 and 2 at 30 or 120 min
prior to challenge with 1 mg/kg ip LPS. Serum TNF-a
levels were measured by ELISA (Table 4).14
4. Pargellis, C.; Regan, J. Curr. Opin. Invest. Drugs 2003, 4,
566.
5. For example, see Sisko, J. J. Org. Chem. 1998, 63,
4529; Liverton, N. J. et al. J. Med. Chem. 1999, 42,
2180; Gill, A. L. et al. J. Med. Chem. 2005, 48,
414.
6. Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.;
Graham, A. G.; Hickey, E.; Klaus, B.; Madwed, J.;
Moriak, M.; Moss, N.; Pargellis, C.; Pav, S.; Proto, A.;
Swinamer, A.; Tong, L.; Torcellini, C. J. Med. Chem.
2002, 45, 2994.
7. Birkofer, L. et al. Chem. Ber. 1972, 105, 1759.
8. Lam, P. Y. S. et al. Tetrahedron Lett. 1998, 39, 2941.
9. We thank Professor Reinhold Tacke and his staff (Institut
Compound 1 (BIRB-796) is effective in this model as dem-
onstrated by TNF-a suppression at both 30 and 120 min.
The silicon compound 2 demonstrated similar efficacy,
particularly at the 30 min time-point, where the levels of
TNF-a were reduced more than compound 1.
fur Anorganische Chemie, Wurzburg, Germany) for
¨
¨
performing the X-ray determination. The details of the
determination have been lodged with the Cambridge
Crystallographic Data Centre (Deposition number
615126).
In conclusion, two new silicon-containing p38 MAP ki-
nase inhibitors (2 and 3) have been described. Com-
pound 2 has been demonstrated to have a good
physicochemical profile and is also comparable in terms
of its stability in human liver microsomes. It appears to
be at least as effective as BIRB-796 with respect to both
in vitro and in vivo activity and therefore is a promising
candidate for further evaluation.
10. See WO 2002 092576 A1.
11. We thank Ian Cooper (Pharmorphix Ltd, Cambridge,
UK) for undertaking these experiments. See the Sup-
plementary Information provided for details of
methods.
12. The p38 MAP kinase enzyme assay was carried out at
Upstate. Details can be found in the Supplementary
Information provided.
13. Microsomal degradation assays were carried out at
Inpharmatica Ltd, Cambridge, UK. Details can be found
in the Supplementary Information provided.
14. The LPS model was conducted by Cerep, France. For
details see Supplementary Information.
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.bmcl.
2006.10.044.