Pyrrolidine and piperidine analogues of SC-57461A as potent, orally active inhibitors of leukotriene A4 hydrolase

Article abstract of DOI:10.1016/S0960-894X(02)00760-6

The synthesis and biological evaluation of a series of functionalized pyrrolidine- and piperidine-containing analogues of our lead LTA₄ hydrolase inhibitor, SC-57461A, is described. A number of compounds showed excellent potency in our in vitro

Full text of DOI:10.1016/S0960-894X(02)00760-6

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3383–3386
Pyrrolidine and Piperidine Analogues of SC-57461A as Potent,
Orally Active 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 Chi-Dean Liang,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 17 June 2002; accepted 3 September 2002
Abstract—The synthesis and biological evaluation of a series of functionalized pyrrolidine- and piperidine-containing analogues of
our lead LTA4 hydrolase inhibitor, SC-57461A, is described. A number of compounds showed excellent potency in our in vitro
screens and several demonstrated good oral activity in a mouse ex vivo assay. These efforts led to the identification of SC-56938 (14)
as a potent, orally active inhibitor of LTA4 hydrolase.
# 2002 Elsevier Science Ltd. All rights reserved.
Leukotriene B4 (LTB4) is a potent, pro-inflammatory
mediator synthesized by a number of cell types and
implicated in the pathogenesis of a number of diseases
including inflammatory bowel disease (IBD), psoriasis,
rheumatoid arthritis and asthma. LTA4 hydrolase is a
zinc-containing enzyme which stereospecifically cata-
lyzes the hydrolysis of the unstable epoxide LTA4 to
LTB4. LTA4 hydrolase represents an attractive target
since the action of this enzyme is the rate limiting step in
the production of LTB4. Anumber of inhibitors of this
enzyme have been reported over the past several years.1
Our previous efforts focused on the exploration of a
series of analogues related to screening hit SC-22716
and resulted in the identification of potent analogues
such as 1.2 The analogues within this non-peptidic series
are unique in that they do not appear to bind zinc as
most other previously reported inhibitors. Extensive
structure–activity studies around this structural class
resulted in the identification of a series of a-, b-, and
g-amino acid analogues that demonstrated potent
inhibition of the LTA4 hydrolase enzyme, as well as
good oral activity in a mouse ex vivo whole blood LTB4
production assay. These efforts led to the identification
of clinical candidate SC-57461A( 2).3ꢀ5
The excellent oral efficacy that was demonstrated with
SC-57461Awe have attributed, at least in part, to the
presence of the carboxylate moiety. Based on this
assumption, we sought to incorporate various polar
functional groups into the cyclic amine moiety of 1 and
12 in an effort to improve upon the generally poor oral
activity demonstrated in this non-functionalized class. A
series of substituted pyrrolidine- and piperidine-con-
taining analogues were synthesized to validate this
hypothesis. In general, all analogues described could be
synthesized as shown in Scheme 1.
*Corresponding author. Tel.: +1-847-982-7563; fax: +1-847-982-
4714; e-mail: thomas.d.penning@pharmacia.com
yCurrently at Abbott Laboratories, Abbott Park, IL, USA.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00760-6

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T. D. Penning et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3383–3386
Scheme 1. General synthesis of functionalized analogues.
Heating tosylate 282 with a variety of functionalized
amines and potassium carbonate in DMF (with cataly-
tic n-Bu4NI optionally added), as previously described,2
provided, after purification by flash chromatography,
the desired cyclic amines. Additional functionalized
analogues were readily accessible by appropriate func-
tional group manipulation. The substituted pyrrolidine
analogues highlighted in Table 1 were synthesized and
evaluated in our recombinant human LTA4 hydrolase
enzyme assay, human whole blood LTB4 production
assay and mouse ex vivo whole blood LTB4 production
assay.4,5 Several analogues showed significant potency
in the enzyme and whole blood assays with two ana-
logues in particular, 6 and 8, also showing good potency
when dosed orally in the mouse ex vivo assay. However,
neither analogue demonstrated the level of potency that
Table 1. In vitro and ex vivo data for pyrrolidino analogues
Compd
R
IC50 (mM)a
Human whole blood
Mouse ex vivo
% inhib @10 mg/kg (ED90
)
rhLTA4 hydrolase
0.026
1
0.12
0.049
1.86
35
2 (SC-57461A)
0.0025
0.45 (2)
4.1
>98 (1–3 mg/kg)
3
0
4
0.23
75
5
0.016
0.39
0.36
60
6
0.24 (2)
0.40
75 (3–10 mg/kg)
7
0.21
4
8
0.081
0.02
0.35
92
57
22
50
9
0.29
10
11
0.21
0.42
0.03 (2)
0.19
aAverage of at least three determinations except where noted in parentheses.

T. D. Penning et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3383–3386
Table 2. In vitro and ex vivo data for piperidino analogues
3385
Compd
R
IC50 (mM)a
Human whole blood
Mouse ex vivo
% inhib @10 mg/kg (ED90
)
rhLTA4 hydrolase
12
0.055 (2)
>3 (1)
1.8
0.17
1.65 (2)
0.82
8
b
13
14 (SC-56938)
97 (3 mg/kg)
15
16
17
18
19
20
0.28
0.13
0.057
0.11
0.087
0.24
0.29
0.64
80
95 (3–10 mg/kg)
92
0.13 (2)
0.70 (2)
0.44
91 (3–10 mg/kg)
72
0.30
91 (3 mg/kg)
21
22
23
24
25
26
27
0.05 (2)
0.47
0.18
0.41
49
56
0.052
1.1
0.58
85
2.4 (2)
0.20
44
0.047
0.015
0.21
50
80 (ꢁ10 mg/kg)
70
0.11
0.79 (2)
aAverage of at least three determinations except where noted in parentheses.
bNot determined.

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T. D. Penning et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3383–3386
was seen with 2. Overall, there was a trend towards
improved oral activity (relative to 1) when a polar
functional group was introduced into the core structure
of 1. However, it appeared that this alone was not suf-
ficient to impart significant oral activity to the molecule,
as evidenced by the complete lack of oral efficacy
demonstrated by 3. Although we attributed poor oral
efficacy, at least in part, to poor oral absorption, this
was not confirmed by any detailed pharmacokinetic
studies.6
piperidine ring system. In general, the 4-carboxypiper-
idine derivatives showed the best overall profile in this
study, with the acid or acid isosteres, ester, and various
amides all demonstrating good oral efficacy in the
mouse ex vivo assay. As a result of this study, SC-56938
was chosen for further biological characterization.
Based on encouraging efficacy data, SC-56938 was
identified as a potential clinical candidate and was
positioned as a backup to the lead LTA4 hydrolase
inhibitor, SC-57461A.
The results for a series of functionalized piperidine-
containing analogues are detailed in Table 2. In general,
3-substituted piperidines such as 13 showed diminished
potency in the enzyme and whole blood assays relative
to the parent structure 12. On the other hand, 4-sub-
stituted analogues 14–23 all showed potencies roughly
equivalent to 12 in the in vitro assays. In addition, all of
the 4-functionalized piperidine analogues demonstrated
significantly improved potency in the mouse ex vivo
assay (relative to 12) including several (14, 16, 18, and
20) with ED90 values in the 3–10 mg/kg range. Several
functionalized bicyclic analogues 25–27 also showed
improved oral efficacy.
References and Notes
1. Penning, T. D. Curr. Pharm. Des. 2001, 7, 163.
2. Penning, T. D.; Chandrakumar, N. S.; Chen, B. B.; Chen,
H. Y.; Desai, B. N.; Djuric, S. W.; Docter, S. H.; Gasiecki,
A. F.; Haack, R. A.; Miyashiro, J. M.; Russell, M. A.; Yu,
S. S.; Corley, D. G.; Durley, R. C.; Kilpatrick, B. F.; Parnas,
B. L.; Askonas, L. J.; Gierse, J. K.; Harding, E. I.; Highkin,
M. K.; Kachur, J. F.; Kim, S. H.; Krivi, G. G.; Villani-Price,
D.; Pyla, E. Y.; Smith, W. G.; Ghoreishi-Haack, N. S. J. Med.
Chem. 2000, 43, 721.
3. Penning, T. D.; Russell, M. A.; Chen, B. B.; Chen, H. Y.;
Liang, C. D.; Mahoney, M. W.; Malecha, J. W.; Miyashiro,
J. M.; Yu, S. S.; Askonas, L. J.; Gierse, J. K.; Harding, E. I.;
Highkin, M. K.; Kachur, J. F.; Kim, S. H.; Villani-Price, D.;
Pyla, E. Y.; Ghoreishi-Haack, N. S.; Smith, W. G. J. Med.
Chem. 2002, 45, 3482.
4. Askonas, L. J.; Kachur, J. F.; Villani-Price, D.; Liang,
C. D.; Russell, M. A.; Smith, W. G. J. Pharmacol. Exp. Ther.
2002, 300, 577.
5. Kachur, J. F.; Askonas, L. J.; Villani-Price, D.; Ghoreishi-
Haack, N.; Won-Kim, S.; Liang, C. D.; Russell, M. A.; Smith,
W. G. J. Pharmacol. Exp. Ther. 2002, 300, 583.
6. Pharmacokinetic data is available for 2, which had an oral
bioavailability of 25% and a half-life of 1.1 h in mouse. How-
ever, the pharmacodynamic half-life as demonstrated in the
mouse ex vivo assay exceeded 24 h, possibly due to its exten-
sive distribution.
Although not particularly potent in our in vitro assays,
but based on the excellent potency demonstrated in the
mouse ex vivo assay, 14 (SC-56938) was chosen for fur-
ther pharmacological evaluation. In a rhesus monkey ex
vivo assay, SC-56938 showed excellent potency when
dosed orally, inhibiting the production of LTB4 with an
ED90 of <10 mg/kg. In addition, SC-56938 was orally
efficacious in a rat peritoneal LTB4 production model,7
with an ED50=3 mg/kg and an ED90=30 mg/kg. Sig-
nificant oral efficacy was also demonstrated in a rat
reversed passive dermal arthus model,7 with an
ED90=3–10 mg/kg.
7. Askonas, L. J.; Kachur, J. F.; Villani-Price, D.; Harding, E.
I.; Pyla, E. Y.; Highkin, M. K.; Liang, D. C.; Desai, B. N.;
Russell, M. A.; Smith, W. G. 8th International Congress of
the Inflammation Research Association, Hersey, PA, 1996;
Abstract 84.
In summary, we have demonstrated that we can sig-
nificantly improve the oral activity of a series of LTA4
hydrolase inhibitors based on 1 and 12 by incorporation
of a polar functional group into the pyrrolidine or