4-Amino-2-cyanopyrimidines: Novel scaffold for nonpeptidic cathepsin S inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.07.011

We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic a

Full text of DOI:10.1016/j.bmcl.2008.07.011

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4642–4646
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
4-Amino-2-cyanopyrimidines: Novel scaffold for nonpeptidic cathepsin S
inhibitors
a
a
a
a
a
Osamu Irie a, , Fumiaki Yokokawa , Takeru Ehara , Atsuko Iwasaki , Yuki Iwaki , Yuko Hitomi ,
Kazuhide Konishi a, Masashi Kishida a, Atsushi Toyao a, Keiichi Masuya a, Hiroki Gunji a, Junichi Sakaki a,
Genji Iwasaki a, Hajime Hirao a, Takanori Kanazawa a, Keiko Tanabe a, Takatoshi Kosaka a,
Terance W. Hart b, Allan Hallett b
*
a Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan
b Novartis Institutes for BioMedical Research, 5 Gower Place, London WC1E 6BS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selec-
tive inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity
toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key
structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group
at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the
pyrimidine.
Received 30 May 2008
Revised 1 July 2008
Accepted 5 July 2008
Available online 10 July 2008
Keywords:
Pyrimidine
Ó 2008 Elsevier Ltd. All rights reserved.
Cathepsin S inhibitors
Nitrile
Cysteine protease
Eleven members of the cysteine cathepsin family have been
identified in the human genome (cathepsins B, C, H, F, K, L, O, S,
V, W, and X).1 Lysosomal cysteine proteases are important
enzymes for processing proteins such as prohormones. Recent
studies on their genes revealed that these cathepsins have specific
individual functions which are important for the normal function-
ing of an organism. These functions are often associated with the
restricted tissue localization of the cathepsins, as demonstrated
for cathepsins S, V, and K. Cathepsin S (Cat S) is predominantly ex-
pressed in spleen, professional antigen presenting cells (APC), such
as dendritic cells, B lymphocytes, and macrophages. The major role
of Cat S in these cells is the processing of the major histocompati-
bility complex (MHC) class II associated invariant chain, which is
essential for the normal functioning of the immune system. Cat S
is largely responsible for the last proteolytic cleavage step of the
invariant chain that produces class II-associated leupeptin induced
peptide (CLIP). Due to its role in the immunological system, Cat S is
an attractive therapeutic target and selective Cat S inhibitors2 may
also modulate a number of other diseases such as rheumatoid
arthritis, multiple sclerosis, myasthenia gravis, asthma, atheroscle-
rosis, and neuropathic pain.3
We have recently reported a novel Cat K inhibitor 1 and its ana-
logs having a 2-cyanopyrimidine scaffold.4 However, 2-cyanopyr-
imidine derivatives were rapidly cleared from the circulation in
Solvent Space
P3
O
1
N
H
N
HN N 2
N
P2
Cat S IC50
Cat K IC50
=
130nM
10nM
=
1
Cat L IC50 = 1100nM
Solvent Space
Solvent Space
R1
O
R3
R3
6
N
N
N
5
H
HN 4
R2
N
2
HN
R2
N
N
N
A
B
or
* Corresponding author. Tel.: +81 29 865 2384; fax: +81 29 865 2308.
E-mail address: osamu.irie@novartis.com (O. Irie).
Figure 1. Design of new 2-cyanopyrimidine Cat S inhibitors.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.011

O. Irie et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4642–4646
4643
O
Cl
Cl
O
O
O
a
b
c
d
N
R
N
R
N
N Cl
R
N
R2
5; R = OMe
N
N
Cl
R2
7; R = OMe
4; R = N(H)(CH2)2Ph 6a-e; R = N(H)(CH2)2Ph 8a-e; R = N(H)(CH2)2Ph
(See : Table 1)
Cl
N
Cl
N
3; R = OMe
2
O
O
R3
N
N
HO
HN
N
e
H
HN
N
N
N
N
9
10a-i
(See : Table 2)
Scheme 1. Reagents and conditions: (a) MeOH or phenethylamine, NEt3, CH2Cl2, 0 °C–rt, 69–86%; (b) R2XH (X = NH or NMe), MeOH, rt–60 °C, 88–98%, or cyclohexylmethanol,
NaH, THF, 0 °C–rt, 32%; (c) NaCN, DABCO, DMSO–H2O, rt–80 °C, 62–96%; (d) LiOH, THF–H2O, 0 °C, 1 h, 33–98%; (e) R3NH2, EDC–HCl, HOAt, DMF, 0 °C–rt, 10 h, 19–88%.
rat pharmacokinetic experiments (PK), and showed low aqueous
solubility. The low solubility is largely due to the lipophilic nature
of compounds that were designed to attractively interact with the
lipophilic active site of cathepsins. There are, however, some
regions in cathepsins that accept polar functional groups. The
effective use of such regions is expected to afford water soluble
Cat S specific inhibitors. After switching the selectivity preference
to Cat S, we thus focused on improving the physicochemical prop-
erties, especially the thermodynamic solubility and the PK profiles,
starting from the 2-cyanopyrimidine compound 1.4 Our strategy
was to add a polar functional group at the 5- or the 6-position
on the pyrimidine ring (Fig. 1). Herein, we describe the details of
the novel scaffold, some of which turned out to be potent and or-
ally bioavailable Cat S inhibitors with suitable PK and physico-
chemical properties.
The synthesis of 5-substituted pyrimidines, type A analogs in
Figure 1, is shown in Scheme 1. Condensation of commercially
available 2,4-dichloropyrimidine-5-carbonyl chloride 2 with meth-
anol, as a protecting group, or phenethylamine as a P3 part gave a
methyl ester 3 and an amide 4. Treatment of P2 amines or sodium
cyclohexylmethoxide with pyrimidine 3 or 4 followed by addition
of sodium cyanide provided methyl ester 7 and compounds 8a–f
(Table 1). Hydrolysis of 7 under basic conditions provided a
Table 2
Optimization of the P3 moiety
O
R3
N
H
N
HN
N
N
a
Compound
R3
IC50 (nM)
Cat S
24
Cat K
Cat L
O
O
10a
>1000
>3000
Ph
O
10b
10c
3
—
840
Ph
N
N
23
200
1500
Ph
N
10d
<1
44
150
Table 1
Ph
Optimization of the P2 moiety
N
O
10e
10f
4
—
480
840
700
510
180
N
H
N
N
R2
N
N
R2
IC50 (nM)
a
Compound
N
21
6
—
Cat S
Cat K
Cat L
Ph
1
Cyclohexyl-NH–
Cyclohexyl-CH2NH–
130
22
32
10
15
36
9
1100
>2000
2000
780
8a
8b
8c
N
Cyclohexyl-CH2N(Me)–-
Cyclohexyl-CH2O–
10g
10h
170
—
14
Ph
F
8d
8e
22
93
15
130
>3000
>3000
>3000
N
CH2NH-
F
7
>3000
>3000
CH2NH-
CH2NH-
Ph
N
10i
2
140
8f
Ph
a
a
Inhibition profiles were determined by a fluorometric assay with recombinant
human Cat K, L, and S, employing Z-Phe-Arg-AMC (Cat K and L) and L-Leu-Leu-Arg-
AMC (Cat S) as synthetic substrates.4
Inhibition profiles were determined by a fluorometric assay with recombinant
human Cat K, L, and S, employing Z-Phe-Arg-AMC (Cat K and L) and L-Leu-Leu-Arg-
AMC (Cat S) as synthetic substrates.4

4644
O. Irie et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4642–4646
compounds 25a–e (Table 3) and 26. Halogenation of compound
26 at the pyrimidine 5-position was achieved by HBr3–pyridine
to provide bromide 27.
OH
OH
b, c, d
R
a
In order to obtain compounds with high potency and selectivity
before exploring the 5- and the 6-substitution on the 2-cyanopyr-
imidine, we initially attempted to optimize the P2 moiety as the S2
subsite of cathepsins is a crucial binding site. The crystal structures
of human Cat S (PDB code 1MS6), K (PDB code 2R6N), and L (PDB
code 3BC3) suggest that the S2 subsite of Cat S is larger due to
the absence of a methyl group on the enzyme compared with that
of Cat K and L.7–9 The S2 subsite in the Cat S enzyme has Gly137
and Gly165, while the corresponding regions in the S2 subsites
in Cat K and L are comprised of Ala134/Ala163 and Ala135/
Gly164, respectively. This structural feature of the Cat S S2 subsite
was considered a clue to the discovery of potent and selective Cat S
inhibitors.
11
12
13 R = NHBoc
e
14 R = NH2
NH2
f, e
OH
NH2
15
b, c
F F
17
F F
16
The result of the SAR study for optimization of the P2 moiety is
shown in Table 1. Lengthening the P2 substituent on the pyrimi-
dine by an additional methylene group gained potency against
Cat S also improving the selectivity to Cat K and L. The cyclohexyl
group was already an appropriate size for a Cat K inhibitor (Table
1; 1 vs 8a). N-Alkylation with a methyl group at the 4-position
on pyrimidine 8b did not give any advantage compared with the
secondary amine 8a. Replacement of the nitrogen atom by oxygen
resulted in a loss of selectivity against Cat L (Table 1; 8a vs 8c).
Substitution of the cyclohexyl ring at the 4-position by difluorides
8d improved selectivity but not the potency. Alternatively
Scheme 2. Reagents and conditions: (a) Et2Zn, CH2I2, toluene, rt–60 °C, 20 h, 34%;
(b) TsCl, NMe3–HCl, NEt3, CH2Cl2, 0 °C–rt, 1 h, quant.; (c) i—NaN3, DMF, rt–60 °C,
3 h; ii—PPh3, THF–H2O, rt, 10 h, 77–99% (2 steps); (d) Boc2O, THF, 0 °C–rt, 0.5 h,
quant; (e) HCl–AcOEt, rt, 0.5 h, quant; (f) H2, PtO2, AcOH, AcOEt, rt, 23 h, 96%.
carboxylic acid 9 as a versatile intermediate for the variation of P3.
Compound 9 was coupled to a variety of P3 amines5 with EDC–HCl
and HOAt to afford the corresponding compounds 10a–i
(Table 2).6
The preparation of 4,4-disubstituted cyclohexylmethyl-amines
14, 15, and 17 is shown in Scheme 2. Simmons-Smith cyclopropa-
nation of commercially available 4-methylenecyclohexylmethanol
11 provided spiro[2.5]oct-6-ylmethanol 12, which was converted
to an amine 14. Hydrogenation of Boc-protected cyclopropane
derivative 13 with PtO2 in AcOH–EtOAc gave 4,4-dim-
ethylcyclohexylmethanol 15 after removal of the Boc group under
acidic conditions. Application of the same condition allowed con-
version of commercially available 4,4-difluorocyclohexylmethanol
16 to 4,4-difluorocyclohexylmethylamine 17.
Table 3
Optimization of the 5- and 6-position on the pyrimidine ring
(CH2)n-
N
O
N
R
N
HN
N
The synthesis of 6-substituted 2-cyano-4-amino-pyrimidines,
type B analogs, is described in Scheme 3. Addition of LDA at
À78 °C to commercially available 4,6-dichloro-2-methylsulfanyl-
pyrimidine 18 in THF followed by treatment of carbon dioxide as
an electrophile afforded a 5-substituted pyrimidine 19. Condensa-
tion of benzylamine, methylamine, or phenethylamine with the
acid chloride derived from carboxylic acid 19 gave amide 20. Intro-
duction of the optimum P2 amine 14–18 and 20 under basic con-
ditions provided 4-amino pyrimidines 22 and 21, respectively.
Conversion of the methyl sulfides to nitriles 23 and 24 was per-
formed by oxidation with mCPBA followed by treatment with
potassium cyanide. Addition of an alkoxy group at the 6-position
on the pyrimidine followed by removal of the Boc group and reduc-
tive amination with HCHO and NaBH3(CN) provided the desired
a
Compound
n
R
IC50 (nM)
Cat S
Cat K
Cat L
25a
25b
25c
25d
25e
26
0
1
2
2
2
2
2
–CONHCH2Ph
–CONHCH2Ph
–CONHCH2Ph
–CONHMe
–CONH(CH2)2Ph
–H
1
—
—
—
—
—
240
100
100
64
270
120
10
<1
<1
2
<1
22
2
870
280
27
–Br
a
Inhibition profiles were determined by a fluorometric assay with recombinant
human Cat K, L, and S, employing Z-Phe-Arg-AMC (Cat K and L) and L-Leu-Leu-Arg-
AMC (Cat S) as synthetic substrates.4
Cl
N
N
(CH2)n-
N
Cl
N
N
18
Cl
N
Cl
N
N
O
N
a
c
d
e
R
R
R
R
N
N
HN
S
Cl
S
Cl
19; R = CO2H
20; R = CON(H)R1
N
S
HN
HN
N
b
25a-e; R = CON(H)R1
(See : Table 3)
26; R = H
21; R = CON(H)R1
22; R = H
23; R = CON(H)R1
24; R = H
c
f
27; R = Br
Scheme 3. Reagents and conditions: (a) LDA, THF, À78 °C, 0.5 h, then CO2, 0.5 h, 98%; (b) (COCl)2, cat. DMF, CH2Cl2, 0 °C–rt, 0.5 h, then BnNH2 or MeNH2 or phenethylamine,
NEt3, THF, 0 °C–rt, 4 h, 78–94%; (c) 14, NEt3, CH2Cl2, rt, 10 h, quant.; (d) i—mCPBA, NaHCO3, CH2Cl2, 0 °C–rt, 10 h; ii—KCN, nBu4N+BrÀ, 18-crown-6, CH2Cl2–H2O, rt, 3 h, 61–77%
(2 steps); (e) i—HO(CH2)n(4-piperazine-NBoc), NaH, THF, 0–60 °C, 6 h, 54–88%; ii—HCl–AcOEt, rt, 0.5 h; iii—HCHO, NaBH3(CN), AcOH, THF, 0 °C–rt, 1.5 h, 47–69%; (f) pyridine–
HBr3, CH2Cl2, rt, 12 h, 89%.

O. Irie et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4642–4646
4645
Figure 2. Designed compounds 10e (type A; left) and 27 (type B; right) docked with the cathepsin S enzyme.
N-methyl piperidine, from the 5- to the 6-position on the pyrimi-
dine ring was well tolerated (Table 2; 10h vs Table 3; 25a). The
ethoxy linker at the 6-position on the pyrimidine had an optimal
based on the potency and selectivity toward Cat S (25a–c). Com-
pound 25c is a sub-nanomolar Cat S inhibitor with excellent selec-
tivity against Cat L (>270-fold). The reduction of lipophilicity on
the P3 moiety by removal of the phenyl ring was also tolerated
(25c vs d), although elongation of the P3 spacer by one methylene
group decreased the selectivity against Cat L despite the well pre-
served sub-nanomolar potency for Cat S (25c vs e). While nonsub-
stitution at the 5-position on the pyrimidine ring significantly
decreased the potency (25c vs 26), replacement of the amide bond
to halogens in order to improve the physicochemical properties
was tolerated in terms of both Cat S affinity and selectivity against
other cathepsins (25 vs 27). In addition, compounds 26 and 27 dis-
Table 4
Thermodynamic solubility (pH 6.8, 25 °C) and pharmacokinetic parameters for 10b, d,
g, and 27 in male Sprague–Dawley rats (iv 1 mg/kg; po 3 mg/kg), where values are
means of n = 3
Compound
Solubility (mg/L)
Cl (L/h/kg)
ivt1/2 (h)
F (%)
poAUCc (nM h)
10b
10da
10gb
27
2
0.8
1.0
10.4
5.1
>8.0
5.7
3.3
4.6
66
42
100
100
2551
916
225
489
27
89
11
a
Single iv; 1 mg/kg and po; 3 mg/kg dose.
iv; n = 2.
Dose-normalized to 1 mg/kg.
b
c
substituting at the 4-position with the bulkier dimethyls 8e de-
creased the potency. The spiro[2.5]oct-6-ylmethyl group, 8f was
an optimum size for the S2 subsite based on both potent and selec-
tivity toward Cat S.
Having identified the optimum P2 moiety, we next explored the
P3 part by a parallel synthesis approach with the key intermediate
9. Our computer-assisted modeling studies suggested that attach-
ment of a polar functional group at the 5-position (type A) or at the
6-position (type B) on the 2-cyanopyrimidine would be tolerated,
because the substituent would orient itself toward the solvent
space (Fig. 2).
The inhibition profiles for type A analogs are shown in Table 2.
Addition of a polar functional group, such as a tertiary amine or an
ether directed toward the solvent space was tolerated (10a, b). Re-
moval of a phenyl group from the lipophilic compounds 10a, b
maintained the potency and selectivity toward Cat S (10d, g–i).
Suitable orientation of the polar functional group increased the po-
tency to Cat S inhibition with over 100-fold selectivity against Cat
L. The absolute configuration of the P3 substitution was crucial for
the inhibitory activity to Cat S (Table 2; 10c vs 10d). Compound
10d is a sub-nanomolar Cat S inhibitor with suitable thermody-
namic solubility (Table 4; 27 mg/L at pH 6.8, 25 °C). The IC50 values
for compounds 10b and 10g were 3 and 6 nM, respectively. Fur-
thermore, 10b, 10d, and 10g exhibited cellular activity as mea-
played potent cellular activity at 1 lM in mouse A20 cells.
Selected compounds were evaluated by PK profiles in cassette
dosing experiments11 in male Sprague–Dawley rats. Representa-
tive PK results, along with thermodynamic solubility (at pH 6.8,
25 °C), are shown in Table 4. Compounds 10d (type A) and 27 (type
B) had excellent bioavailabilities (42% and 100%) and low clear-
ances (1.0 and 5.1 L/h/kg, respectively) with acceptable thermody-
namic aqueous solubility (27 and 11 mg/L, respectively).
In summary, two types of novel compounds having a 2-cyano-
pyrimidine scaffold were derived from the Cat K inhibitors, leading
us to the development of sub-nanomolar Cat S inhibitors with
excellent selectivity against Cat L. The compounds had potent cel-
lular activity in mouse A20 cells as well as suitable physicochem-
ical and PK profiles. The in vivo activity of these series in rodent
will be reported in future publications.
Acknowledgments
We thank Michie Kobayashi, Tomoko Ohkubo, Andrew McB-
ryde, Caroline Huntley, Prafula Copp, and Hendrikus Eggelete for
excellent technical assistance. The authors are grateful to Christo-
pher R. Snell, Pamposh Ganju, and Shinichi Koizumi for valuable
discussions.
sured by invariant chain (Ii) degradation at 1
lM in mouse A20
cells.10
References
As shown in Table 3, introduction of a substituent at the 6-posi-
tion on pyrimidine (type B in Fig. 1) also provided excellent Cat S
inhibition. The replacement of a polar functional group, such as
1. For recent reviews of Cat S, see: Gupta, S.; Singh, R. K.; Dastidar, S.; Ray, A.
Expert Opin. Ther. Targets 2008, 12, 291; Maryanoff, B. E.; Costanzo, M. J. Bioorg.
Med. Chem. 2008, 16, 1562.

4646
O. Irie et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4642–4646
2. For recent cathepsin S inhibitors, see: Gauthier, J. Y.; Black, W. C.; Courchesne,
I.; Cromlish, W.; Desmarais, S.; Houle, R.; Lamontagne, S.; Li, C. S.; Massé, F.;
McKay, D. J.; Ouellet, M.; Robichaud, J.; Truchon, J.-F.; Truong, V.-L.; Wang, Q.;
Percival, M. D. Bioorg. Med. Chem. Lett. 2007, 17, 4929; Chatterjee, A. K.; Liu, H.;
Tully, D. C.; Guo, J.; Epple, R.; Russo, R.; Williams, J.; Roberts, M.; Tuntland, T.;
Chang, J.; Gordon, P.; Hollenbeck, T.; Tumanut, C.; Li, J.; Harris, J. L. Bioorg. Med.
Chem. Lett. 2007, 17, 2899; Bekkali, Y.; Thomson, D. S.; Betageri, R.; Emmanuel,
M. J.; Hao, M.-H.; Hickey, E.; Liu, W.; Patel, U.; Ward, Y. D.; Young, E. R. R.;
Nelson, R.; Kukulka, A.; Brown, M. L.; Crane, K.; White, D.; Freeman, D. M.;
Labadia, M. E.; Wildeson, J.; Spero, D. M. Bioorg. Med. Chem. Lett. 2007, 17, 2465;
Wei, J.; Pio, B. A.; Cai, H.; Meduna, S. P.; Sun, S.; Gu, Y.; Jiang, W.; Thurmond, R.
L.; Karlsson, L.; Edwards, J. P. Bioorg. Med. Chem. Lett. 2007, 17, 5525; Inagaki,
H.; Tsuruoka, H.; Hornsby, M.; Lesley, S. A.; Spraggon, G.; Ellman, J. A. J. Med.
Chem. 2007, 50, 2693; Irie, O.; Ehara, T.; Iwasaki, A.; Yokokawa, F.; Sakaki, J.;
Hirao, H.; Kanazawa, T.; Teno, N.; Horiuchi, M.; Umemura, I.; Gunji, H.; Masuya,
K.; Hitomi, Y.; Iwasaki, G.; Nonomura, K.; Tanabe, K.; Fukaya, H.; Kosaka, T.;
Snell, C. R.; Hallett, A. Bioorg. Med. Chem. Lett. 2008, 18, 3959.
3. (a) Clark, A. K.; Yip, P. K.; Grist, J.; Gentry, C.; Staniland, A. A.; Marchand, F.;
Dehvari, M.; Wotherspoon, G.; Winter, J.; Ullah, J.; Bevan, S.; Malcangio, M.
Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 10655; (b) Barclay, J.; Clark, A. K.; Ganju,
P.; Gentry, C.; Patel, S.; Wotherspoon, G.; Buxton, F.; Song, C.; Ullah, J.; Winter,
J.; Fox, A.; Bevan, S.; Malcangio, M. Pain 2007, 130, 225.
4. Altmann, E.; Aichholz, R.; Betschart, C.; Buhl, T.; Green, J.; Irie, O.; Teno, N.;
Lattmann, R.; Tintelnot-Blomley, M.; Missbach, M. J. Med. Chem. 2007, 50, 591.
5. Suzuki coupling reaction between commercially available 2-bromo-4,5-
dimethoxy phenylamine and phenylboronic acid with a catalytic amount of
Pd(PPh3)4 with Na2CO3 in dioxane–H2O at 100 °C gave an aniline intermediate
for preparing 10a. Synthesis of an aniline intermediate for 10b is described in
our patent application.6 Amines for 10c, d, g, and h are commercially available
reagents. For syntheses of amines 10e and 10f from commercially available
amino acid derivatives, see: Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127,
10504; For preparation of an amine for 10i see: Jiang, X.-H.; Song, Y.-L.; Long,
Y.-Q. Bioorg. Med. Chem. Lett. 2004, 14, 3765.
6. New compounds have been characterized by 1H NMR and MS. The
experimental information is described in our patent application, see: Hart, T.
W.; Hallett, A.; Yokokawa, F.; Hirao, H.; Ehara, T.; Iwasaki, A.; Sakaki, J.;
Masuya, K.; Kishida, M.; Irie, O. WO 2006018284, 2006.
7. Pauly, T. A.; Sulea, T.; Ammirati, M.; Sivaraman, J.; Danley, D. E.; Griffor, M. C.;
Kamath, A. V.; Wang, I.-K.; Laird, E. R.; Seddon, A. P.; Menard, R.; Cygler, M.;
Rath, V. L. Biochemistry 2003, 42, 3203.
8. Teno, N.; Miyake, T.; Ehara, T.; Irie, O.; Sakaki, J.; Ohmori, O.; Gunji, H.; Matsuura,
N.; Masuya, K.; Hitomi, Y.; Nonomura, K.; Horiuchi, M.; Gohda, K.; Iwasaki, A.;
Umemura, I.; Tada, S.; Kometani, M.; Iwasaki, G.; Cowan-Jacob, S. W.; Missbach,
M.; Lattmann, R.; Betschart, C. Bioorg. Med. Chem. Lett. 2007, 17, 6096.
9. Chowdhury, S. F.; Sivaraman, J.; Wang, J.; Devanathan, G.; Lachance, P.; Qi, H.;
Ménard, R.; Lefebvre, J.; Konishi, Y.; Cygler, M.; Sulea, T.; Purisima, E. O. J. Med.
Chem. 2002, 45, 5321.
10. Riese, R. J.; Wolf, P. R.; Brömme, D.; Natkin, L. R.; Villadangos, J. A.; Ploegh, H. L.;
Chapman, H. A. Immunity 1996, 4, 357.
11. (a) Manitpisitkul, P.; White, R. E. Drug Discovery Today 2004, 9, 652; (b) Janser,
P.; Neumann, U.; Miltz, W.; Feifel, R.; Buhl, T. Bioorg. Med. Chem. Lett. 2006, 16,
2632.