A new 4-(2-methylquinolin-4-ylmethyl)phenyl P1′ group for the β-amino hydroxamic acid derived TACE inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.01.041

A new P1′ group for TACE inhibitors was identified by eliminating the oxygen atom in the linker of the original 4-(2-methylquinolin-4-ylmethoxy)phenyl P1′ group. Incorporation of this 4-(2-methylquinolin-4-ylmethyl)phenyl group onto different β-aminohydro

Full text of DOI:10.1016/j.bmcl.2007.01.041

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1865–1870
A new 4-(2-methylquinolin-4-ylmethyl)phenyl P10 group for
the b-amino hydroxamic acid derived TACE inhibitors
Xiao-Tao Chen,a,* Bahman Ghavimi,a Ronald L. Corbett,a Chu-Biao Xue,a Rui-Qin Liu,b
Maryanne B. Covington,b Mingxin Qian,c Krishna G. Vaddi,c David D. Christ,c
Karl D. Hartman,c Maria D. Ribadeneira,c James M. Trzaskos,b
Robert C. Newton,b Carl P. Deciccoa and James J.-W. Duana
aDiscovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
bDiscovery Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
cPharmaceutical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
Received 27 November 2006; revised 11 January 2007; accepted 12 January 2007
Available online 24 January 2007
Abstract—A new P10 group for TACE inhibitors was identified by eliminating the oxygen atom in the linker of the original 4-(2-
methylquinolin-4-ylmethoxy)phenyl P10 group. Incorporation of this 4-(2-methylquinolin-4-ylmethyl)phenyl group onto different
b-aminohydroxamic acid cores provided compound 18, which demonstrated potent porcine TACE (p-TACE) and human whole
blood activity, excellent PK properties, and good selectivity against a variety of MMPs.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Tumor necrosis factor-a (TNF-a) is a pro-inflammatory
cytokine, which plays a key role in initiating defensive
immune responses upon exposure to diverse pathogens.1
The pathological properties of over-expressed TNF-a
have been well documented for diseases, such as rheu-
matoid arthritis,2 Crohn’s disease,3 psoriasis,4 and septic
shock.5 The clinical success of the anti-TNF-a biologics
for the treatment of rheumatoid arthritis,6 Crohn’s dis-
ease,7 and psoriasis8 has provided validation for sup-
pressing the circulating TNF-a as a therapeutic target.
Thus, there has been broad interest in pursuing small
molecules to intervene in the circulating TNF-a produc-
tion. One such target is TNF-a converting enzyme
(TACE),9 which is responsible for the shedding of solu-
ble TNF-a from membrane-bound pro-TNF-a.
TNF-a release in vivo upon endotoxin stimulation.11
At the early stage of TACE discovery program, efforts
were focused on the improvement of TACE potency
through rational drug design based on MMP inhibi-
tors.12 Given the toxicity observed with most broad
spectrum MMP inhibitors in the clinic,13 recent efforts
have been directed toward achieving TACE selectivity
over MMPs. As a result, a number of potent and
selective TACE inhibitors have been identified.14
More recently, we disclosed a number of constrained
b-amino hydroxamic acids as potent and selective
TACE inhibitors (1, 2, and 3) (Fig. 1),15 that contain
H
N
O
The initial leads of TACE inhibitor disclosed in the
literature were derived from broad spectrum MMP
inhibitors, due to high sequence similarity in the active
site regions of TACE and MMPs.10 In fact, prior to
the discovery of TACE in 1997, some synthetic hydroxa-
mate-based inhibitors of MMPs were found to block
HN
HO
N
H
O
O
N
1
H
N
O
O
O
O
N
HO
N
H
N
H
H
HN
OH
O
O
O
N
N
Keywords: Anti-inflammatory agent; TACE inhibitor; Matrix metallo-
proteinase inhibitor; b-Amino hydroxamic acid.
Corresponding author. Tel.: +1 609 252 3049; fax: +1 609 252
6804; e-mail: xiao-tao.chen@bms.com
2
3
*
Figure 1. Previously disclosed b-amino hydroxamic acids as potent
TACE inhibitors.
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.01.041

1866
X.-T. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1865–1870
the 4-(2-methylquinolin-4-ylmethoxy)phenyl P10 group.
A campaign to identify alternatives to this P10 group
was also carried out. Our goal was to identify either a
different heterocycle replacement for the quinoline or
an alternative linker between the phenyl and quinolinyl
groups. Our efforts to identify different heterocycle
replacements for the 2-methylquinoline group were
recently disclosed.16 Herein, we wish to describe our
efforts on modification of the linker region, which even-
tually led to the identification of the 4-(2-methylquino-
lin-4-ylmethyl)phenyl as an effective P10 group.
netic property as demonstrated at the early stage of this
program, we tried to improve both Caco-2 permeability
and WBA potency in parallel in our SAR investigation.
Increasing the bulk of the substituent from methyl to
isobutyl (9) and neopentyl (10) gradually improved the
Caco-2 permeability, but compromised WBA activity.
A propargyl group or a 2-butynyl group on the pyrrol-
idine nitrogen provided analogs 11 and 12, which dem-
onstrated potent WBA activity and acceptable cell
permeability. Analogs with a pivaloyl (13), a 1-but-
anesulfonyl (14) or a methoxycarbonyl (15) substituent
on the pyrrolidine nitrogen retained potency in the
WBA, but exhibited poor cell permeability. The potent
WBA activities and the acceptable cell permeability of
11 and 12 prompted us to evaluate these two compounds
in rat N-in-1 PK studies (N compounds in one dosage)18
(Table 3). Although both of these compounds showed
similar oral bioavailability (Fpo 19–20%), 11 exhibited
a much shorter half-life and lower oral drug exposure
compared to 12, which is attributed to the relatively
higher clearance associated with 11.
The initial structure–activity relationships (SAR) were
carried out on the 4-aminopyrrolidine-3-carbohydroxa-
mic acid series with a one-atom linker and the results
are shown in Table 1. Using the TACE inhibitor 1 as
a reference compound since it was potent in both por-
cine TACE assay (p-TACE)9b,17 (IC50 = 6.3 nM) and
human whole blood cell assay (WBA) (IC50 = 75 nM),
shortening the tether length by removal of the methylene
group gave compounds 4 and 5, which retained activity
against p-TACE (IC50 values of 1.3 and 3.5 nM for 4
and 5, respectively). However, this alteration resulted
in a 10-fold loss in WBA potency. In contrast, the meth-
ylene linker analogs (i.e., compounds 6 and 7) had com-
parable biological activities in both p-TACE assay and
WBA compared to the reference compound 1. These re-
sults revealed that the two-atom linker in compound 1
can be shortened by eliminating the oxygen, but not
the methylene group. Based on these results, further
SAR studies were focused on the left-hand side of the
molecule while keeping the new P10 substituent with
the methylene linker constant.
Next, we examined the effectiveness of incorporating the
4-(2-methylquinolin-4-ylmethyl)phenyl P10 group onto
other carbocycle or heterocycle cores.15 As shown in
Table 4, all of the compounds except 16 were potent
against p-TACE. 16 was a weak inhibitor of p-TACE
and completely inactive up to 3 lM in the WBA. A com-
parison of the two five-membered cyclic compounds 17
and 19 revealed that the more polar tetrahydrofuran
ring was superior to the less polar cyclopentane ring in
terms of WBA activity. 17, however, was inferior to 19
in the Caco-2 permeability assay. The six-membered
tetrahydropyran ring provided potent WBA activity
and acceptable Caco-2 permeability. Compound 18 also
demonstrated favorable PK properties with high oral
drug exposure and good oral bioavailability in rat and
dog (Table 5).
The SAR involving replacement of the hydrogen on the
pyrrolidine nitrogen in compound 7 with different sub-
stituents is provided in Table 2. A variety of groups,
such as methyl (8), branched alkyl (9–10), propargyl
(11–12), pivaloyl (13), 1-butanesulfonyl (14), and alk-
oxycarbonyl (6, 15), were well tolerated, affording IC50
values of 1.1–4.3 nM. However, the WBA potency and
the cell permeability of these compounds were depen-
dent on the nature of the substituents. The methyl com-
pound 8 showed potent WBA activity but low Caco-2
permeability. Since low caco-2 permeability of a TACE
inhibitor had consistently resulted in poor pharmacoki-
Because of the most favorable in vitro potencies and PK
properties of 18, we examined its selectivity profile
against a panel of MMPs (Table 6). Compound 18
was selective against the MMPs in the panel.
In an attempt to improve the profile of 18, we investigat-
ed the effect of substitution on the quinoline ring. With
Table 1. Biological evaluation of analogs with an oxygen and methylene linker
R
N
O
HN
HO
N
N
H
O
X
Compound
R
X
p-TACEa IC50 (nM)
WBAb IC50 (nM)
1
4
5
6
7
H
–CO2-t-Bu
–OCH2–
–O–
–O–
6.3 1.6
1.3 0.3
3.5 1.1
<1
75 22
750 180
920 180
96 14
H
–CO2-t-Bu
–CH2–
–CH2–
H
<1
67 17
a (n = 2–6).
b (n = 3–12).

X.-T. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1865–1870
Table 2. SAR on the 4-amino-pyrrolidine 3-carbohydroxamic acid seriesa
1867
R
N
O
HN
HO
N
N
H
O
Compound
R
p-TACEb IC50 (nM)
2.5 0.6
WBAc IC50 (nM)
96 14
Caco-2 X10ꢀ6 cm/s
8
Me
0.3
1.5
9.3
0.7
1.9
0
9
10
11
12
13
14
15
1.6 0.4
1.6 0.3
4.3 1.1
1.0 0.2
1.5 0.3
1.1 0.3
3.3 1.0
220 69
700 94
86 25
110 35
95 24
120 45
50 15
O
O O
S
0.3
0.1
O
O
a All of the compounds were selective over MMP-1 (>5.0 lM), MMP-2 (>3.0 lM), MMP-9 (>2.0 lM) and MMP-13 (>5.0 lM).
b (n = 2–6).
c (n = 3–12).
Table 3. Pharmacokinetic parameters of 11 and 12 in rat N-in-1 study (N compounds in one dosage study)
iv
Dose (mg/kg)
t1/2 (h)
Cl (L/h/kg)
Vss (L/kg)
AUC (nM h)
11
12
5.0
5.0
0.6
2.9
2.2
0.3
0.8
0.1
5100
27,000
po
11
12
Dose (mg/kg)
tmax (h)
0.25
0.25
AUC (nM h)
962
5270
F (%)
19
20
5.0
5.0
Table 4. The effectiveness of the new P10 group on different coresa
R=
N
Compound
Structure
p-TACEb IC50 (nM)
WBAc IC50 (nM)
Caco-2 · 10ꢀ6 cm/s
O
O
O
O
16
97 24
>3000
HO
N
N
H
R
R
H
O
H
N
17
18
19
2.0 0.5
130 36
0.1
0.6
1.2
HO
N
H
O
O
O
1.0 0.3
130 24
HN
HN
HO
R
O
O
H
N
1.8 0.4
560 130
HO
N
R
H
O
a All of the compounds were selective over MMP-1 (>5.0 lM), MMP-2 (>3.0 lM), MMP-9 (>2.0 lM), and MMP-13 (>5.0 lM).
b (n = 2–6).
c (n = 3–12).

1868
X.-T. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1865–1870
Table 5. Pharmacokinetic parameters of 18 in rat and dog
iv
Dose (mg/kg)
t1/2 (h)
Cl (L/h/kg)
Vss (L/kg)
AUC (nM h)
Rat
Dog
4.0
2.0
1.7
3.7
0.5
2.1
0.5
7.1
19000
2300
po
Dose (mg/kg)
tmax (h)
3.0
9.5
AUC (nM h)
15000
5900
F (%)
39
64
Rat
Dog
8.0
8.0
five-membered cycle (i.e., 29), potent p-TACE and
WBA activities were observed. Introducing an oxygen
atom in the tricyclic portion of 29 (i.e., 30 and 31) had
little effect on the potency of both p-TACE and WBA.
Table 6. Selectivity profile of 18
Enzyme
IC50 (nM)
Enzyme
IC50 (nM)
MMP-1
MMP-2
MMP-3
MMP-7
MMP-8
>5000
>3000
1800
MMP-9
>2000
2400
MMP-10
MMP-13
MMP-14
MMP-15
>5000
>5000
>7000
The synthesis of compound 18 started from the commer-
cially available 4-hydroxy-2-methylquinoline (32), as
illustrated in Scheme 1. Compound 32 was treated with
phosphorus oxytribromide to give the corresponding
bromide 33. Treatment of the resulting bromide with
n-BuLi at ꢀ78 ꢁC in THF, followed by the addition of
a solution of methyl 4-formylbenzoate, afforded the
carbinol 34. Deoxygenation of 34 was achieved using a
two-step procedure. First, 34 was treated with MsCl
and triethylamine in dichloromethane. Second, hydroge-
nation of the resulting mesylate under 1 atm of H2 in the
presence of 10 % Pd/C in MeOH led to 35. Hydrolysis of
35 was achieved under basic conditions to afford the
corresponding acid 36, which was coupled with
1700
>3000
Table 7. SAR on quinoline with 4-aminotetrahydropyran 3-carbohy-
droxamic acid core
O
O
N
N
H
HN
O
R1
OH
R2
Compound R1
R2
p-TACEaIC50 WBAb IC50
(nM)
(nM)
20
21
22
23
24
25
26
27
28
CF3
Et
H
2.2 0.4
1.7 0.4
<1.0
260 78
78 27
(3R,4R)-methyl
4-aminotetrahydro-2H-pyran-3-car-
H
boxylate 3815a to give intermediate 37. Conversion of
37 to the corresponding hydroxamic acid 18 was carried
out with hydroxylamine under basic conditions.
i-Pr
Morpholinyl
H
420 72
720 190
460 150
230 58
98 22
H
1.6 0.1
1.2 0.4
1.3 0.3
1.5 0.5
1.2 0.4
7.8 2.6
Me2N
Cyclopropyl
H
H
A more concise synthetic strategy utilizing 4-methoxy-
carbonylbenzyl zinc bromide19 was developed for the
synthesis of compound 25 (Scheme 2). Using the
Conrad–Limpach quinoline synthesis,20 2-cyclopropyl-
4-hydroxyquinoline (41) was assembled from aniline 39
and b-ketoester 40 in two steps. Compound 41 was con-
verted to the triflate 42 upon treatment with LHMDS
H
Me
Me
Et
Me
Me
85 17
1200 400
29
30
31
1.0 0.2
2.6 0.7
1.3 0.1
72 10
87 26
77 27
O
O
and
N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trif-
luoromethylsulfonyl)methanesulfonamide. Intermediate
42 was reacted with zinc reagent 4319 to provide
compound 44. Hydrolysis of 44 under basic conditions,
a (n = 2–6).
b (n = 3–12).
the tetrahydropyran core (Table 7), substitutions on the
R1 and R2 positions were generally tolerated for
p-TACE activity, regardless of the electronic-nature and
the bulk of the substituents. However, the WBA potency
was highly dependent on the nature of the groups. While
the electronic-deficient group (CF3), electronic-rich
groups (NMe2, morpholinyl), and bulky groups (i-Pr
and c-Pr) decreased the WBA potency, 2-ethyl (21),
3-methyl (26), and 2,3-dimethyl (27) substituents on
the quinoline retained the activity. When the 2-position
on the quinoline was substituted with a methyl group, a
slightly longer alkyl substituent (i.e., an ethyl) than a
methyl group at the 3-position was detrimental to
p-TACE and especially to WBA as seen with 28. When
the methyl and ethyl groups in 28 were tethered into a
Scheme 1. Reagents and conditions: (a) POBr3, 160 ꢁC, 12 h, 40%; (b)
n-BuLi, THF, ꢀ78 ꢁC, then methyl 4-formylbenzoate, 65%; (c) MsCl,
TEA, DCM; (d) 10% Pd/C, H2, MeOH, >95% over two steps; (e) 1 N
NaOH, MeOH, 60 ꢁC, >95%; (f) BOP, DIEA, DCM, 97%; (g)
NH2OHÆHCl, NaOMe, MeOH, 55%.

X.-T. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1865–1870
1869
Widmer, M. B.; Blosch, C. M. N. Engl. J. Med. 1997, 337,
141.
7. Lipsky, P. E.; van der Heijde, D. M.; St. Clair, E. W.;
Furst, D. E.; Breedveld, F. C.; Kalden, J. R.; Smolen, J.
S.; Weisman, M.; Emery, P.; Feldmann, M.; Harriman, G.
R.; Maini, R. N. N. Engl. J. Med. 2000, 343, 1594.
8. Leonardi, C. L.; Powers, J. L.; Matheson, R. T.; Goffe, B.
S.; Zitnik, R.; Wang, A.; Gottlieb, A. B. N. Engl. J. Med.
2003, 349, 2014.
9. (a) Black, R. A.; Rauch, C. T.; Kozlosky, C. J.; Peschon,
J. J.; Slack, J. L.; Wolfson, M. F.; Castner, B. J.; Stocking,
K. L.; Reddy, P.; Srinivasan, S.; Nelson, N.; Boiani, N.;
Schooley, K. A.; Gerhart, M.; Davis, R.; Fitzner, J. N.;
Johnson, R. S.; Paxton, R. J.; March, C. J.; Cerretti, D. P.
Nature 1997, 385, 729; (b) Moss, M. L.; Jin, C. S.-L.;
Milla, M. E.; Burkhart, W.; Carter, H. L.; Chen, W.-J.;
Clay, W. C.; Didsbury, J. R.; Hassler, D.; Hoffman, C. R.;
Kost, T. A.; Lambert, M. H.; Leesnitzer, M. A.; McCau-
ley, P.; McGeehan, G.; Mitchell, J.; Moyer, M.; Pahel, G.;
Rocque, W.; Overton, L. K.; Schoenen, F.; Seaton, T.; Su,
J.-L.; Warner, J.; Willard, D.; Becherer, J. D. Nature 1997,
385, 733.
10. Wasserman, Z. R.; Duan, J. J.; Voss, M. E.; Xue, C.-B.;
Cherney, R. J.; Nelson, D. J.; Hardman, K. D.; Decicco,
C. P. Chem. Biol. 2003, 10, 215, and references cited
therein.
11. Mohler, K. M.; Sleath, P. R.; Fitzner, J. N.; Cerretti, D.
P.; Alderson, M.; Kerwar, S. S.; Torrance, D. S.; Otten-
Evans, C.; Greenstreet, T.; Weerawarna, K.; Kronheim, S.
R.; Petersen, M.; Gerhart, M.; Kozlosky, C. J.; March, C.
J.; Black, R. A. Nature 1994, 370, 218.
12. (a) Xue, C.-B.; He, X.; Corbett, R. L.; Roderick, J.;
Wasserman, Z.; Liu, R.-Q.; Jaffee, B. D.; Covington, M.
B.; Qian, M.; Trzaskos, J. M.; Newton, R. C.; Magolda,
R. L.; Wexler, R. R.; Decicco, C. P. J. Med. Chem. 2001,
44, 3351; (b) Rabinowitz, M. H.; Andrews, R. C.;
Becherer, J. D.; Bickett, D. M.; Bubacz, D. G.; Conway,
J. G.; Cowan, D. J.; Gaul, M.; Glennon, K.; Lambert, M.
H.; Leesnitzer, M. A.; McDougald, D. L.; Moss, M. L.;
Musso, D. L.; Rizzolio, M. C. J. Med. Chem. 2001, 44,
4252; (c) Holms, J.; Mast, K.; Marcotte, P.; Elmore, I.; Li,
J.; Pease, L.; Glaser, K.; Morgan, D.; Michaelides, M.;
Davidsen, S. Bioorg. Med. Chem. Lett. 2001, 11, 2907; (d)
Chen, J. M.; Jin, G.; Sung, A.; Levin, J. I. Bioorg. Med.
Chem. Lett. 2002, 12, 1195; (e) Cherney, R. J.; Duan, J. J.-
W.; Voss, M. E.; Chen, L.; Wang, L.; Meyer, D. T.;
Wasserman, Z. R.; Hardman, K. D.; Liu, R.-Q.; Coving-
ton, M. B.; Qian, M.; Mandlekar, S.; Christ, D. D.;
Trzaskos, J. M.; Newton, R. C.; Magolda, R. L.; Wexler,
R. R.; Decicco, C. P. J. Med. Chem. 2003, 46, 1811.
13. (a) Wojtowicz-Praga, S.; Torri, J.; Johnson, M.; Steen, V.;
Marshall, J.; Ness, E.; Dickson, R.; Sale, M.; Rasmussen,
H. S.; Chiodo, T. A.; Hawkins, M. J. J. Clin. Oncol. 1998,
16, 2150; (b) Levitt, N. C.; Eskens, F. A.; O’Byrne, K. J.;
Propper, D. J.; Denis, L. J.; Owen, S. J.; Choi, L.;
Foekens, J. A.; Wilner, S.; Wood, J. M.; Nakajima, M.;
Talbot, D. C.; Steward, W. P.; Harris, A. L.; Verweij
J. Clin. Cancer Res. 2001, 7, 1912.
Scheme 2. Reagents and conditions: (a) p-TsOHÆH2O, PhH; (b) Ph2O,
250 ꢁC, 27% over two steps; (c) LHMDS, N-(5-chloropyridin-2-yl)-
1,1,1-trifluoro-N-(trifluoromethyl sulfonyl)methanesulfonamide, THF,
79%; (d) LiCl, Pd(PPh3)4, DMF, 45%; (e) 1 N NaOH, MeOH, 84%; (f)
BOP, DIEA, DCM, 92%; (g) NH2OHÆHCl, NaOMe, MeOH, 50%.
followed by coupling with b-amino ester 38, gave rise to
the product 46. Treatment of 46 with hydroxylamine un-
der basic conditions provided the corresponding
hydroxamic acid 25. The compounds disclosed in Tables
1, 2, 4, and 7 were synthesized in a similar manner as de-
scribed in Schemes 1 and 2, substituting 38 with different
cyclic b-amino ester.21
In conclusion, we have successfully identified 4-(2-meth-
ylquinolin-4-ylmethyl)phenyl as an effective P10 group
for TACE inhibitors by eliminating the oxygen atom
in the linker of the original 4-(2-methylquinolin-4-
ylmethoxy)phenyl P10 group. Incorporating the new
P10 group onto different b-aminohydroxamic acid cores
provided a new series of TACE inhibitors with potent
WBA activity. Among them, compound 18 was identi-
fied to have good PK properties and an excellent selec-
tivity profile over the MMPs.
Acknowledgments
The authors thank John Giannaras, Sherrill A. Nurn-
berg, Dianna L. Blessington, Persymphonie B. Miller,
Theresa M. Dimeo, Robert J. Collins, Tracy L. Taylor,
and Paul J. Strzemienski for performing in vitro and
in vivo assays. The authors also thank Dr. Robert
Borzilleri for his editorial assistance.
References and notes
1. (a) Vassalli, P. Annu. Rev. Immunol. 1992, 10, 411; (b)
Szatmary, Z. Neoplasma 1999, 46, 257.
2. William, R. O.; Feldmann, M.; Maini, R. N. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 9784.
14. (a) Xue, C.-B.; He, X.; Roderick, J.; Corbett, R. L.; Duan,
J. J.-W.; Liu, R.-Q.; Covington, M. B.; Qian, M.;
Ribadeneira, M. D.; Vaddi, K.; Christ, D. D.; Newton,
R. C.; Trzaskos, J. M.; Magolda, R. L.; Wexler, R. R.;
Decicco, C. P. Bioorg. Med. Chem. Lett. 2003, 13, 4299;
(b) Xue, C.-B.; He, X.; Roderick, J.; Corbett, R. L.; Duan,
J. J.-W.; Liu, R.-Q.; Covington, M. B.; Newton, R. C.;
Trzaskos, J. M.; Magolda, R. L.; Wexler, R. R.; Decicco,
C. P. Bioorg. Med. Chem. Lett. 2003, 13, 4293; (c) Levin, J.
I.; Chen, J. M.; Du, M. T.; Nelson, F. C.; Killar, L. M.;
Skala, S.; Sung, A.; Jin, G.; Cowling, R.; Barone, D.;
3. Murch, S. H.; Braeger, C. P. Gut 1993, 34, 1705.
4. Ettehadi, P.; Greaves, M. W.; Wallach, D.; Aderka, D.;
Camp, R. D. Clin. Exp. Immunol. 1994, 96, 146.
5. (a) Dinarello, C. A. J. Infect. Dis. 1991, 163, 1177; (b)
Cannon, J. G.; Tompkins, R. G.; Gelfand, J. A.; Michie,
H. R.; Stanford, G. G.; van der Meer, J. W.; Endres, S.;
Lonnemann, G.; Corsetti, J.; Chernow, B. J. Infect. Dis.
1990, 161, 79.
6. Moreland, L. W.; Baumgartner, S. W.; Schiff, M. H.;
Tindall, E. A.; Fleischmann, R. M.; Weaver, A. L.;
Ettlinger, R. E.; Cohen, S.; Koopman, W. J.; Mohler, K.;

1870
X.-T. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1865–1870
March, C. J.; Mohler, K. H.; Black, R. A.; Skotnicki, J. S.
Duan, J. J.-W. Abstracts of Papers, 228th ACS National
Meeting, Philadelphia, PA, USA, 2004, August 22–26,
MEDI-324; (c) Gilmore, J. L.; King, B. W.; Harris, C.;
Maduskuie, T. P.; Mercer, S. E.; Liu, R.-Q.; Covington,
M. B.; Qian, M.; Ribadeneria, M. D.; Vaddi, K. G.;
Trzaskos, J. M.; Newton, R. C.; Decicco, C. P.; Duan, J.
J.-W. Bioorg. Med. Chem. Lett. 2006, 16, 2699.
Bioorg. Med. Chem. Lett. 2002, 12, 1199; (d) Letavic, M.
A.; Axt, M. Z.; Barberia, J. T.; Carty, T. J.; Danley, D. E.;
Geoghegan, K. F.; Halim, N. S.; Hoth, L. R.; Kamath, A.
V.; Laird, E. R.; Lopresti-Morrow, L. L.; McClure, K. F.;
Mitchell, P. G.; Natarajan, V.; Noe, M. C.; Pandit, J.;
Reeves, L.; Schulte, G. K.; Snow, S. L.; Sweeney, F. J.;
Tan, D. H.; Yu, C. H. Bioorg. Med. Chem. Lett. 2002, 12,
1387; (e) Duan, J. J. W.; Chen, L.; Wasserman, Z. R.; Lu,
Z.; Liu, R.-Q.; Covington, M. B.; Qian, M.; Hardman, K.
D.; Magolda, R. L.; Newton, R. C.; Christ, D. D.; Wexler,
R. R.; Decicco, C. P. J. Med. Chem. 2002, 45, 4954; (f)
Duan, J. J.-W.; Lu, Z.; Xue, C.-B.; He, X.; Seng, J. L.;
Roderick, J. J.; Wasserman, Z. R.; Liu, R.-Q.; Covington,
M. B.; Magolda, R. L.; Newton, R. C.; Trzaskos, J. M.;
Decicco, C. P. Bioorg. Med. Chem. Lett. 2003, 13, 2035.
16. (a) Ott, G. R.; Asakawa, N.; Lu, Z.; Anand, R.; Liu, R.;
Covington, M.; Vaddi, K.; Qian, M.; Duan, J. J.-W.
Abstracts of Papers, 230th ACS National Meeting, Wash-
ington, DC, USA, 2005, August 28–September 1, MEDI-
289; (b) Lu, Z.; Anand, R.; Liu, R.; Covington, M.; Vaddi,
K.; Qian, M.; Duan, J. J.-W.; Ott, G. R. Abstracts of
Papers, 230th ACS National Meeting, Washington, DC,
USA, 2005, August 28–September 1, MEDI-288.
17. Xue, C.-B.; He, X.; Roderick, J.; Degrado, W. F.;
Cherney, R. J.; Hardman, K. D.; Nelson, D. J.; Copeland,
R. A.; Jaffee, B. D.; Decicco, C. P. J. Med. Chem. 1998, 41,
1745, and references cited therein.
18. Liang, L.; Chi, C.; Wright, M.; Timby, D.; Unger, S. Am.
Biotech. Lab. 1999, 17, 8.
19. Shiota, T.; Yamamori, T. J. Org. Chem. 1999, 64, 453.
20. Reynolds, G. A.; Hauser, C. R. Org. Syn. 1949, 29, 70,
and references cited therein.
15. (a) Duan, J. J.-W.; Ott, G. R.; King, B.W.; Maduskuie, T.
P.; Xue, C.-B.; Chen, L.; Lu, Z.; Gilmore, J. L.; Asakawa,
N.; Mercer, S. E.; Xu, M.; Harris, C. M.; Wasserman, Z.
R.; Liu, R.-Q.; Covington, M. B.; Qian, M.; Vaddi, K. G.;
Christ, D. D.; Hardman, K. D.; Ribadeneira, M. D.;
Newton, R. C.; Trzaskos, J. M.; Decicco, C. P. Abstracts
of papers, 226th ACS National Meeting, New York, NY,
USA, 2003, September 7–11, MEDI-201; (b) Ott, G. R.;
Lu, Z.; Asakawa, N.; Covington, M. B.; Qian, M.; Liu,
R.-Q.; Newton, R. C.; Christ, D. D.; Decicco, C. P.;
21. Ott, G.; Chen, X.-T.; Duan, J.; Lu, Z. PCT Int. Appl. WO
2003024899A2, 2003.