Synthesis of imidazopyridines and purines as potent inhibitors of leukotriene A4 hydrolase

Article abstract of DOI:10.1016/S0960-894X(03)00039-8

The synthesis and biological evaluation of a series of heterocyclic analogues of the previously reported LTA₄ hydrolase inhibitor 1b are described. Imidazopyridine and purine analogues are specifically highlighted with several demonstrating excellent potency in our in vitro assays, as well as good oral activity in a mouse ex vivo assay.

Full text of DOI:10.1016/S0960-894X(03)00039-8

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1137–1139
Synthesis of Imidazopyridines and Purines as Potent Inhibitors of
Leukotriene A4 Hydrolase
Thomas D. Penning,a,* Nizal S. Chandrakumar,a Bipin N. Desai,a Stevan W. Djuric,a,y
Alan F. Gasiecki,a James W. Malecha,a Julie M. Miyashiro,a Mark A. Russell,a
Leslie J. Askonas,b James K. Gierse,b Elizabeth I. Harding,b Maureen K. Highkin,b
James F. Kachur,b Suzanne H. Kim,b Doreen Villani-Price,b E. Yvonne Pyla,b
Nayereh S. Ghoreishi-Haackb and Walter G. Smithb
aDepartment of Medicinal Chemistry, Pharmacia Corporation, 4901 Searle Parkway, Skokie, IL 60077, USA
bDepartments of Inflammatory Diseases Research and Molecular Pharmacology, Pharmacia Corporation, 4901 Searle Parkway,
Skokie, IL 60077, USA
Received 4 September 2002; accepted 18 December 2002
Abstract—The synthesis and biological evaluation of a series of heterocyclic analogues of the previously reported LTA4 hydrolase
inhibitor 1b are described. Imidazopyridine and purine analogues are specifically highlighted with several demonstrating excellent
potency in our in vitro assays, as well as good oral activity in a mouse ex vivo assay.
# 2003 Elsevier Science Ltd. All rights reserved.
Leukotriene B4 (LTB4) is a potent, pro-inflammatory
mediator implicated in the pathogenesis of a number of
diseases including inflammatory bowel disease (IBD),
psoriasis, rheumatoid arthritis and asthma. Akey
enzyme in the biosynthesis of LTB4 is LTA4 hydrolase,
a zinc-containing enzyme which stereospecifically cata-
lyzes the hydrolysis of LTA4 to LTB4. LTA4 hydrolase
is an attractive target since the action of this enzyme is
the rate limiting step in the production of LTB4. We,
along with several others have reported a number of
inhibitors over the past several years.1 Our previous
efforts focused on the exploration of a series of analo-
gues related to screening hit 1a (SC-22716) and resulted
in the identification of potent analogues such as 1b.2
These non-peptidic analogues are unique in that they do
not appear to bind zinc as most other previously repor-
ted inhibitors. Extensive structure–activity studies
around this structural class resulted in the identification
of a series of acyclic and cyclic amino acid analogues
that demonstrated potent inhibition of the LTA4
hydrolase enzyme. More significantly, these analogues
also showed good oral activity in a mouse ex vivo whole
blood LTB4 production assay, and led to the identifi-
cation of clinical candidates 2 (SC-57461A)3ꢀ5 and 3
(SC-56938).6,7
To further investigate the SAR around the amine moiety
of this series, we incorporated a number of nitrogen-
containing heterocycles as replacements for the pyrroli-
dine group in the core molecule 1b. Since the excellent
oral efficacy demonstrated with 2 and 3 was attributed
in part to the presence of the carboxylate moiety, we
also investigated the incorporation of additional polar
functionality into these heterocyclic series. The moder-
ate potency demonstrated with imidazole 4, led us to
*Corresponding author. Tel.: +1-847-982-7563; fax: +1-847-982-
4714; e-mail: thomas.d.penning@pharmacia.com
yCurrent address: Abbott Laboratories, Abbott Park, IL, USA.
explore
a series of bicyclic imidazole-containing
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00039-8

1138
T. D. Penning et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1137–1139
Table 1. In vitro and ex vivo data of heterocyclic analogues
Compd
R
IC50 (mM)a
Mouse ex
vivo % inhib
@10 mg/kg
rhLTA4
hydrolase
Human
whole blood
Scheme 1. General synthesis of imidazopyridine and purine
analogues.
0.026
0.12
1.34
35
29
1b
4
0.12
analogues, most notably, imidazopyridines and purines.
The general synthesis of these analogues is outlined in
Scheme 1. Heating either tosylate 13a or chloride 13b2
with the appropriate nitrogen-containing heterocycle
and potassium carbonate in DMF, as previously
described,2 provided the desired alkylation product(s).
In the case of the imidazopyridine and purine analo-
gues, all possible regioisomeric products were obtained
and were separated by flash chromatography. In gen-
eral, further functionalization of the imidazopyridine
adducts could be carried out as described in Scheme 2.
Oxidation with m-CPBAprovided N-oxide 14. Treat-
ment with trifluoroacetic anhydride8 yielded pyridone
15, whereas treatment with TMSCN9,10 gave nitrile 16.
The unfunctionalized analogues were evaluated in our
recombinant human LTA4 hydrolase enzyme assay,
human whole blood LTB4 production assay and mouse
ex vivo whole blood LTB4 production assay and the
data is detailed in Table 1.4,5 In general, most analogues
showed similar potency to 1b in both enzyme and whole
blood assays. However, within each series, there were
specific regioisomers that stood out in terms of enzyme
potency (i.e., 6b, 7c, 8b and 8c). Although we saw no
improvement in mouse ex vivo potency with 4, 5 and 6a/b/
c (relative to 1), we did see significant potency improve-
ments with 7b/c and 8a/b/d, up to 72 and 76% inhibi-
tion of LTB4 production at a 10 mg/kg dose for 8d and
7c, respectively. The results for several functionalized
imidazopyridine analogues are shown in Table 2. In
general, all of these analogues showed a significant
increase in potency in both the enzyme assay and whole
blood assays, with nitrile 12 showing subnanomolar
potency in the enzyme assay. In addition, several of the
analogues demonstrated an improvement in potency in
the mouse ex vivo assay, with 9a, 9b, 10, and 11 all
inhibiting LTB4 production >70% at a 10 mg/kg oral
dose.
5
2.0 (2)
13.2 (2)
9.15 (2)
46
b
6a
>3 (2)
6b
6c
0.008 (2)
0.14
0.33
0.69
18
22
7a
0.56
0.73
39
7b
7c
8a
0.12
0.011
0.73
0.33
0.074
0.14
64
76
60
8b
8c
8d
0.047
0.04
0.18
0.79
0.14
0.46
57
b
72
aAverage of at least three determinations except where noted in
parentheses.
bNot determined.
In summary, we have described a series of nitrogen-
containing heterocyclic analogues of some of our pre-
viously reported LTA4 hydrolase inhibitors. We have
demonstrated that we can replace the cyclic amine moi-
ety from the earlier series with these heterocycles and
Scheme 2. Functionalization of imidazopyridines.

T. D. Penning et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1137–1139
1139
Table 2. In vitro and ex vivo data of functionalized heterocyclic
analogues
References and Notes
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IC50 (mM)a
Mouse ex
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@10 mg/kg
rhLTA4
hydrolase
Human
whole blood
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0.32 (2)
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maintain good potency in both the enzyme and human
whole blood assays. Several of these heterocyclic ana-
logues also exhibited an increase in potency in the
mouse ex vivo assay. In addition, we have demon-
strated that further functionalization of these hetero-
cycles improved enzyme inhibitory potency, as well as
mouse ex vivo potency.