(+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist.

Article abstract of DOI:10.1021/jm980046r

By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds wer

Full text of DOI:10.1021/jm980046r

1970
J . Med. Chem. 1998, 41, 1970-1979
(()-tr a n s-2-[3-Meth oxy-4-(4-ch lor op h en ylth ioeth oxy)-5-(N-m eth yl-N-
h yd r oxyu r eid yl)m eth ylp h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tetr a h yd r ofu r a n
(CMI-392), a P oten t Du a l 5-Lip oxygen a se In h ibitor a n d P la telet-Activa tin g
F a ctor Recep tor An ta gon ist
Xiong Cai,*,† Ralph T. Scannell,† David Yaeger,† Md. Sajjat Hussoin,† David B. Killian,† Changgeng Qian,†
J oseph Eckman,† San-Bao Hwang,† Lynn Libertine-Garahan,† C. Grace Yeh,† Stephen H. Ip,† and T. Y. Shen‡
CytoMed, Inc., 840 Memorial Drive, Cambridge, Massachusetts 02139, and Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22903
Received J anuary 21, 1998
By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series
of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating
factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro
for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism
in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid- and TPA-
induced ear edema in mice were used to determine in vivo activities. The structure-activity
relationship analysis to define a preclinical lead is presented. (()-trans-2-[3-methoxy-4-(4-
chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphe-
nyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-
induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor)
or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a
physical combination of the latter two agents. These results suggest that a single compound
which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide
therapeutic advantages over single-acting agents. The clinical development of compound 40
is in progress.
In tr od u ction
Leukotrienes (LTs) are potent lipid mediators pro-
duced by the oxidation of arachidonic acid by 5-lipoxy-
genase (5-LO).1 LTB4, C4, D4, and E4 play major roles
in inflammatory and allergic responses.2,3 For example,
LTB4, a potent chemotactic agent for neutrophils and
eosinophils, is an important mediator of inflammation.4
LTC4, D4, and E4 are potent bronchoconstrictors, as well
as the slow-reacting substance of anaphylaxis.5 Platelet-
activating factor (PAF) is a potent inflammatory phos-
pholipid mediator with a wide variety of biological
activities.6,7 It is generated and released by many
inflammatory cells, as well as by renal and cardiac
tissues under appropriate immunological and nonim-
munological stimulation,8 and it appears to play a
pathological role during immune and inflammatory
responses in a number of disorders.9
As both LTs and PAF are potent proinflammatory
mediators induced under similar pathological condi-
tions, the administration of a mixture of 5-LO inhibitor
and PAF antagonist may provide an effective antiin-
flammatory therapeutic.10 From cost and pharmaco-
dynamic considerations, a single compound which both
inhibits LT synthesis and blocks PAF activity, if fea-
sible, could offer therapeutic advantages over a mixture
of single acting agents.
F igu r e 1. Design of dual 5-lipoxygenase inhibitor and PAF
receptor antagonist.
reported.11-13 The introduction of a hydroxyurea func-
tionality onto certain scaffolds has been shown to confer
5-LO inhibitory activity, possibly involving chelation of
Fe3+ required for catalysis.13 To optimize dual 5-LO
inhibition and PAF receptor antagonist activities in a
single compound, we have incorporated an N-hydroxy-
urea functionality onto a well-characterized family of
PAF receptor antagonists, the 2,5-diaryltetrahydro-
furans (Figure 1). A number of hydroxyureidyl deriva-
tives of diaryltetrahydrofurans have been synthesized
in our laboratories previously, which show dual 5-LO
inhibitory and PAF receptor antagonistic activities.14-17
In this paper, we describe the discovery of (()-trans-2-
[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-
N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphe-
nyl)tetrahydrofuran (40, CMI-392) as a potent dual
5-LO inhibitor and PAF receptor antagonist which is
currently being evaluated in human clinical trials as a
novel antiinflammatory agent.
A number of monofunctional and dual functional 5-LO
inhibitors and PAF receptor antagonists have been
* Author for correspondence.
† CytoMed, Inc.
‡ University of Virginia.
S0022-2623(98)00046-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/29/1998

CMI-392: A Potent Dual 5-Lipoxygenase Inhibitor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1971
Sch em e 1a
a
(a) ICH2CH2OH, K2CO3, 18-crown-6, DMF, 4; (b) ICH2CH2OH, NaH, DMF; (c) 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride,
Et3N 4; (d) NaBH4, THF, CH3OH, H2O; (e) CF3COOH, CHCl3; (f) CH3SO2Cl, Et3N, CH2Cl2.
Ch em istr y
thioether compounds with magnesium monoperoxyph-
thalic acid (MMPP) in the yield of 53%, 67%, and 63%,
respectively.
The preparation of the key intermediates 10 and 11
is shown in Scheme 1. Compound 1 was obtained in
three steps from 3,4,5-trimethoxyacetophenone as pre-
viously described.18 Compounds 2 and 3 were prepared
by alkylation of 5-nitrovanillin and 5-iodovanillin with
iodoethanol in 23% and 93% yield, respectively. Con-
densation of 1 and 2 or 1 and 3 in the presence of
thiazolium catalyst and triethylamine gave 1,4-dike-
tones 4 (60% yield) and 5 (51% yield), respectively.
Reduction of the diketones 4 and 5 with sodium boro-
hydride in methanol and tetrahydrofuran gave the
corresponding 1,4-diols 6 (99% yield) and 7 (99% yield).
The diols 6 and 7 were then cyclized with 5% trifluo-
roacetic acid in chloroform at 0 °C to give a mixture of
cis and trans isomers of 2,5-diaryltetrahydrofurans
which were separated by column chromatography to
give the desired trans isomers 8 and 9 in 21% and 41%
yield, respectively. The mesylation of 8 and 9 with
methanesulfonyl chloride and triethylamine in dichlo-
romethane gave the key intermediates 10 (99% yield)
and 11 (77% yield).
The conversion of intermediate 10 to the final sub-
stituted hydroxyureidyldiaryltetrahydrofurans is shown
in Scheme 2. Heating 10 with a variety of substituted
thiophenols, triethylamine, and ethanol gave 12-18 in
a yield between 82% and 95%. Reduction of these nitro
compounds with zinc, calcium chloride, and ethanol gave
the corresponding amines 19-25 in 69% to 94% yields.
Compounds 19-25 were then treated with triphosgene
followed by n-butylhydroxylamine to give compounds
26-32 in a yield between 43% and 85%. The sulfones
33, 34, and 35 were prepared from the corresponding
The final substituted hydroxyureidyltetrahydrofurans
synthesized from intermediate 11 are shown in Scheme
3. Treatment of 11 with 4-chlorothiophenol yielded 36
in 87% yield. Reaction of 36 with CuCN in DMF gave
37 (90% yield). Reduction of 37 with sodium borohy-
dride and boron trifluoride etherate gave the amine 38
in 21% yield. Treatment of 38 with triphosgene, fol-
lowed by n-butylhydroxylamine gave 39 (32% yield).
Similar treatment of 38 with methylhydroxylamine
yielded 40 in 80% yield.
Resu lts a n d Discu ssion
Compounds described in this paper were evaluated
in several in vitro and in vivo assays. The in vitro
assays included PAF receptor binding,18 5-LO enzyme
inhibition using rat basophilic leukemic (RBL) cell
extracts, and the inhibition of LTB4 production in
human whole blood (HWB).19,20 The in vivo assays were
PAF-induced hemoconcentration21 and arachidonic acid-
induced ear edema in mice.22,23 The results are sum-
marized in Tables 1 and 2.
We have previously synthesized CMI-206 (41) and its
analogues.16 The biological data indicate that trans
isomers are always more potent than the corresponding
cis isomers in antagonizing PAF, but there is little
difference between the trans and corresponding cis
isomers for inhibiting 5-LO. The n-butyl chain on the
ureidyl group also produces potent overall activity.16
Accordingly, the essential features of the trans isomers
with an n-butylhydroxyureidyl chain at C-5 on ring B

1972 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Ta ble 1. In Vitro Activity of Selected Hydroxyurea Compounds
Cai et al.
IC50 (nM)
HWBd
IC50 (µM)
compda
26
27
28
29
30
31
32
n
Z
R
X
PAFb
5-LOc
Inh (%)
0
0
0
0
0
0
0
0
0
0
1
1
S
S
S
S
S
S
S
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3
4-Cl
3,4-Cl
4-Br
2-Br
3-Br
2,3,5,6-F
4-OMe
4-Br
2-Br
2,3,5,6-F
4-Cl
20
45
21
23
22
2
39
38
25
285
167
10
33
6
58
17
19
33
43
118
71
ND*
161
520
ND*
100
424
6.5
1.2
7.5
61
48
3
32
72
19
ND*
26
33
34
35
39
40
41
SO2
SO2
SO2
S
S
4-Cl
7.8
3.5
MK 287e
WEB 2086f
zileutong
A-78773g
94
804
298
1.0
0.1
a
All synthetic compounds (26-40) had C, H, N or C, H, N, S analyses (0.4% the theoretical except 33 which has the following: Anal.
(C33H41O10N2SBr) C, H, N; C: calcd, 53.73; found, 53.20. PAF receptor antagonist activity was determined by competition of [3H]PAF
b
specific binding to human platelet membranes. c 5-LO inhibitory activity was determined by measuring the conversion of [14C]arachidonic
d
acid to leukotrienes in RBL-2H3 cell using thin-layer chromatography. HWB assay was done by measuring the production of LTB4 in
calcium ionophore (A 23187)-activated human whole blood by the enzyme immunoassay. The percent inhibition was measured at 3 µM.
g
e Obtained from Merck Research Laboratories. f Obtained from Boehringer-Ingelheim laboratories. Obtained from Abbott Research
Laboratories. *ND ) not determined.
were retained, and further modifications were made at
C-4 of ring B. When the C-4 propoxyl group on ring B
was replaced by a substituted phenylthioethoxyl group
(compounds 26-32), the 5-LO activity was significantly
increased while the PAF activity remained undimin-
ished (Table 1).
both in PAF binding (IC50 ) 285 nM) and 5-LO inhibi-
tion (IC50 ) 520 nM) assays. The compounds with a
halogen (X ) Cl, Br, F) substituted phenylthioethoxy
chain on ring B (26-31) are more potent than the
methoxy substituted analogue (32) in overall 5-LO
inhibition and PAF binding assays.
In Vivo Mod els. The compounds were further tested
in in vivo models (Table 2). The 4- bromo analogue 28,
which is very active in the HWB assay, showed no
activity in both PAF-induced hemoconcentration and
arachidonic acid-induced ear edema models. To test the
hypothesis that this might be caused by metabolic
oxidation of thioether to sulfone, the corresponding
sulfone derivative 33 was made and tested in these two
models and showed increased activity. To determine if
a sulfone substituent might generally offer more ad-
vantages in vivo, two other pairs of sulfide and sulfone
analogues were synthesized (31 and 35, 29 and 34). The
data shows that 31 and 35 have almost the same
activity in PAF-induced hemoconcentration model, but
the thioether 31 has higher potency in the arachidonic
acid-induced ear edema model and in in vitro assays.
Compound 34 is inactive in the arachidonic acid-induced
ear edema model while compound 29 is active. Fur-
thermore, 29 is 5 times more potent than 34 in the in
vitro 5-LO assay (Tables 1 and 2). These results
diminished our further interests in pursuing the sulfone
analogues.
In Vitr o Assa ys. The in vitro activity of the com-
pounds are listed in Table 1. All of the compounds
tested are potent PAF receptor antagonists. The 2,3,5,6-
tetrafluoro-substituted compound (31) is the most potent
PAF receptor antagonist (IC50 ) 2 nM) among those
prepared, being about 3 times more potent than MK
287. However, 31 is less potent in 5-LO inhibition with
an IC50 value of 118 nM in the RBL assay and only 3%
inhibition at 3 µM in the HWB assay. The correspond-
ing sulfone derivative 35 showed much lower potency
In the design of a dual functional molecule, a balanced
activity profile with both 5-LO inhibition and PAF
antagonism is desirable. An analysis of our structure-
activity data indicated that monohalogen substitution
is preferable and a para substituent in the sulfur-
attached phenyl ring is also important for stabilizing

CMI-392: A Potent Dual 5-Lipoxygenase Inhibitor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1973
Sch em e 2a
and chronic TPA-induced mouse ear edema assays, as
summarized in Table 3. Topical treatment of compound
40 in the acute and chronic TPA models resulted in a
significant decrease of ear weight, inflammatory cell
infiltration (as assessed by MPO content), and histologi-
cal examination (data not shown).
Compound 40 was also tested in the arachidonic acid-
induced mouse ear edema model in comparison with a
5-LO inhibitor (zileuton), a PAF receptor antagonist (BN
50739)25 and a combination of zileuton and BN 50739
(Figure 2). The results indicate that 40 is more potent
than either zileuton or BN 50739 and that 40 achieves
an equivalent inhibitory effect as a physical combination
of the latter two. These results suggest that a dual
function compound which both inhibits 5-LO and an-
tagonizes PAF receptor binding may provide therapeutic
advantages over agents with only single biological
activity (5-LO or PAF). Compound 40 has accordingly
been advanced to clinical development as a novel
antiinflammatory agent.
Exp er im en ta l Section
Ch em istr y. Gen er a l. Proton nuclear magnetic resonance
spectra were recorded on a Varian Gemini-300 spectrometer
at ambient temperature in CDCl3 and proton chemical shifts
are relative to tetramethylsilane (TMS) as an internal stan-
dard. Melting points were determined on a Electrothermal
IA 9100 melting point apparatus in open capillary tube and
are uncorrected. Elemental analyses were performed by
Atlantic Microlab, Inc., Norcross, GA. Silica gel 60 (E. Merck,
230-400 mesh) was used for flash column chromatography.
THF was freshly distilled from sodium benzophenone ketyl.
DMF and ethanol were anhydrous grade. Other solvents were
HPLC grade. All the other chemicals were from commercial
suppliers and used without further purification.
3-Meth oxy-4-h yd r oxyeth oxy-5-n itr oben za ld eh yd e (2).
To a solution of 5-nitrovanillin (25 g, 126.8 mmol) in DMF (650
mL) was added potassium carbonate (21.0 g, 152.2 mmol) and
18 crown-6 (3.35 g, 12.68 mmol). The mixture was heated to
80 °C to make a clear solution. 2-Iodoethanol (43.61 g, 253.6
mmol) was added, and the reaction mixture was stirred at 80
°C for 48 h. The reaction was diluted with water and extracted
with ethyl acetate. The organic layer was washed with water
and brine, dried over MgSO4, filtered, and evaporated to give
the title compound as an oil (7.1 g, 23%): 1H NMR δ 3.68 (bs,
1H), 3.94 (m, 2H), 4.02 (s, 3H), 4.45 (t, J ) 4.1 Hz, 2H), 7.65
(d, J ) 1.6 Hz, 1H), 7.92 (d, J ) 1.6 Hz, 1H), 9.95 (s, 1H).
3-Meth oxy-4-h yd r oxyeth oxy-5-iod oben za ld eh yd e (3).
To a stirred suspension of NaH (60% dispersion in mineral
oil) (3.60 g, 90.0 mmol) in dimethylformamide (25 mL) was
added dropwise a solution of 5-iodovanillin (25 g, 90.0 mmol)
in DMF (100 mL) at 0 °C. The reaction mixture was stirred
at 0 °C for 30 min and then allowed to warm to room
temperature. 2-Iodoethanol (23.1 g, 134.3 mmol) was added
dropwise. After the addition, the reaction mixture was stirred
at 50 °C for 20 h. The reaction was quenched with water and
extracted with ethyl acetate. The organic layer was washed
with aqueous NaOH (10%), water, and saturated NaCl, dried
over MgSO4, filtered, and evaporated in vacuo to yield 3 as a
tan solid (26.8 g, 93%) which was used without further
purification: 1H NMR δ 3.91 (m, 2H), 3.94 (s, 3H), 4.29 (t, J )
4.1 Hz, 2H), 7.42 (s, 1H), 7.88 (s, 1H), 9.84 (s, 1H).
a
(a) Et3N, EtOH, HS-C6H4-R, R ) 4-Cl or 3,4-Cl or 4-Br or 2-Br
or 3-Br or 2,3,5,6-F or 4-OCH3, reflux; (b) Zn, CaCl2, EtOH, reflux;
(c) (Cl3CO)2CO, EtOH, CH2Cl2, reflux; (d) CH3(CH2)3NHOH, Et3N,
CH2Cl2; (e) MMPP, CH3CN, H2O.
the compound against metabolism. Therefore, com-
pound 26 was considered to be a good lead candidate in
this series meeting both of these criteria.
Com p ou n d 40. The next attempts were made to
improve the activity of compound 26, especially in the
in vivo models. We focused on the hydroxyurea side
chain on ring B. Compound 39 was formed by inserting
a methylene group between ring B and the hydroxyurea
side chain of compound 26. As a consequence, however,
the PAF receptor binding affinity of 39 decreased
significantly. Compound 39 also showed only 26%
inhibition at 3 µM in the human whole blood assay.
However, when the n-butyl chain was replaced by a
methyl group to form compound 40, it showed very
potent and balanced activities against both 5-LO and
PAF. Compared with reference compounds, 40 is more
potent than zileuton and A-78773 in 5-LO inhibitory
activity and is more potent than WEB 2086 and almost
equally potent as MK 287 in PAF receptor antagonist
activity.
1-(3-Meth oxy-4-h yd r oxyeth oxy-5-n itr op h en yl)-4-(3,4,5-
tr im eth oxyp h en yl)-1,4-bu ta n ed ion e (4). A mixture of 1
(22 g, 99.1 mmol), 2 (19.9 g, 82.6 mmol), and 3-benzyl-5-(2-
hydroxyethyl)-4-methylthiazolium chloride (8.9 g, 33.1 mmol)
in triethylamine (105 mL) were stirred at 60 °C for 16 h. The
reaction was then acidified with 10% HCl and extracted with
dichloromethane and the organic layer washed with 10% HCl,
water, and saturated NaCl solution. The extract was dried
over MgSO4, filtered, and evaporated in vacuo to yield 4 as a
crude solid (23 g, 60%) which was used for the next reaction
Compound 40 was further studied in several 5-LO
inhibition and PAF antagonism assays, including acute

1974 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Cai et al.
Sch em e 3a
a
(a) HS-C6H4-p-Cl, Et3N, EtOH, reflux; (b) CuCN, DMF, 4; (c) NaBH4, BF3‚Et2O, THF, reflux or BH3THF, THF, reflux; (d) (Cl3CO)2CO,
Et3N, CH2Cl2, reflux; (e) CH3CH2CH2CH2NHOH, Et3N, CH2Cl2; (f) CH3NHOHHCl, Et3N, CH2Cl2.
Ta ble 2. In Vivo Activity of Selected Hydroxyurea Compounds
inhibition (%), 3 mg/kg
compd
n
Z
R
X
PAF-Htca
AA-Edb
26
27
28
29
30
31
32
33
34
35
40
0
0
0
0
0
0
0
0
0
0
1
S
S
S
S
S
S
S
SO2
SO2
SO2
S
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3CH2CH2CH2
CH3
4-Cl
3,4-Cl
4-Br
2-Br
3-Br
2,3,5,6-F
4-OMe
4-Br
2-Br
2,3,5,6-F
4-Cl
43
26
-11
34
28
59
24
29
39
26
-3
26
40
30
3
35
-9
12
46
60
50
56
a
PAF-induced hemoconcentration in mice was evaluated by measuring the hematocrit. Animals were challenged with PAF, iv, 15 min
b
after dosing with compound, iv. Arachidonic acid-induced ear edema in mice was determined by measuring the ear weight following the
topical application of arachidonic acid 15 min after intravenous administration of compound.
without further purification: 1H NMR δ 3.43 (m, 4H), 3.92
(m, 2H), 3.93 (s, 9H), 4.00 (s, 3H), 4.42 (t, J ) 4.2 Hz, 2H),
7.29 (s, 2H), 7.80 (d, J ) 1.8 Hz, 1H), 8.11 (d, J ) 1.8 Hz, 1H).
methanol (240 mL) was added dropwise sodium borohydride
(1.18 g, 31.2 mmol) in water (60 mL). The reaction was stirred
at room temperature for 3 h, the reaction mixture was cooled
in an ice-water bath and quenched with water, and the
aqueous layer was extracted with ethyl acetate. The organic
layer was dried over MgSO4, filtered, and evaporated to
provide 6 as a foam (8.0 g, 99%) which was used directly in
the next step.
1-(3-Meth oxy-4-h yd r oxyeth oxy-5-iod op h en yl)-4-(3,4,5-
tr im eth oxyp h en yl)-1,4-bu ta n ed iol (7). To a stirred solu-
tion of 5 (11.6 g, 21.3 mmol) in tetrahydrofuran (120 mL) and
methanol (240 mL) was added dropwise the sodium borohy-
dride (1.45 g, 38.4 mmol) in water (60 mL). The reaction was
stirred at room temperature for 2.5 h, cooled in an ice-water
bath, and quenched with water, and the aqueous layer was
extracted with ethyl acetate. The organic layer was dried over
MgSO4, filtered, and evaporated to provide the title product
as a foam (11.8 g, 99%) which was used directly in the next
step: 1H NMR δ 1.86 (m, 4H), 3.83 (s, 3H), 3.86 (m, 2H), 3.87
(s, 9H), 4.15 (m, 2H), 4.68 (m, 2H), 6.57 (s, 2H), 6.90 (s, 1H),
7.32 (s, 1H).
1-(3-Meth oxy-4-h yd r oxyeth oxy-5-iod op h en yl)-4-(3,4,5-
tr im eth oxyp h en yl)-1,4-bu ta n ed ion e (5). A mixture of 1
(4.8 g, 21.6 mmol), 3 (5.7 g, 17.8 mmol), and 3-benzyl-5-(2-
hydroxyethyl)-4-methylthiazolium chloride (1.9 g, 7.0 mmol)
in triethylamine (20 mL) was stirred at 60 °C for 16 h. The
reaction was then acidified with 10% HCl and extracted with
dichloromethane. The organic layer was washed with 10%
HCl, water, and saturated NaCl solution. The organic layer
was dried over MgSO4, filtered, and evaporated in vacuo to
give 5 as a crude solid (9.7 g, 51%) which was carried to the
next step without further purification: 1H NMR δ 3.41 (m,
4H), 3.90 (m, 2H), 3.92 (s, 3H), 3.93 (s, 9H), 4.26 (t, J ) 4.4
Hz, 2H), 7.29 (s, 2H), 7.57 (d, J ) 1.8 Hz, 1H), 8.08(d, J ) 1.8
Hz, 1H).
1-(3-Meth oxy-4-h yd r oxyeth oxy-5-n itr op h en yl)-4-(3,4,5-
tr im eth oxyp h en yl)-1,4-bu ta n ed iol (6). To a stirred solu-
tion of 4 (8.0 g, 17.3 mmol) in tetrahydrofuran (120 mL) and

CMI-392: A Potent Dual 5-Lipoxygenase Inhibitor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1975
Ta ble 3. In Vitro and in Vivo Activity of Compound 40
mL) at 0 °C was added dropwise trifluoroacetic acid (9.82 g,
86.1 mmol) in chloroform (100 mL) over 30 min. The solution
was stirred at 0 °C for 2 h and then at room temperature for
1 h. The reaction was quenched with 1 N NaOH, and
chloroform (100 mL) was added. The organic layer was
washed with 1 N NaOH solution, water, and saturated NaCl
solution, dried over MgSO4, filtered, and evaporated in vacuo
to an oil which was a cis and trans mixture. The trans isomer
9 was isolated as an oil by flash column chromatography (silica
gel, 1:1 hexane/ethyl acetate) (4.7 g, 41%) as the faster eluting
isomer: 1H NMR δ 1.98 (m, 2H), 2.45 (m, 2H), 3.83 (s, 3H),
3.86 (m, 2H), 3.88 (s, 9H), 4.15 (t, J ) 4.4 Hz, 2H), 5.17 (m,
2H), 6.61 (s, 2H), 6.96 (s, 1H), 7.38(d, 1H).
(±)-tr a n s-2-(3-Meth oxy-4-m eth a n esu lfon yleth oxy-5-n i-
t r op h en yl)-5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r ofu r a n
(10). To a stirred solution of 8 (1.64 g, 3.65 mmol) in
dichloromethane (80 mL) at 0 °C were added methanesulfonyl
chloride (627.5 mg, 5.48 mmol) and triethylamine (553.3 mg,
5.48 mmol). The reaction was stirred at 0 °C for 2 h, water
was added, and the reaction was extracted with ethyl acetate.
The organic layer was washed with water and brine and
evaporated to an oil which was purified by flash column
chromatography (silica gel, 1:1 hexane/ethyl acetate) to yield
10 as an oil (1.9 g, 99%): 1H NMR δ 2.00 (m, 2H), 2.50 (m,
2H), 3.10 (s, 3H), 3.86 (s, 3H), 3.89 (s, 6H), 3.96 (s, 3H), 4.42
(t, J ) 4.5 Hz, 2H), 4.58 (t, J ) 4.5 Hz, 2H), 5.23 (m, 2H), 6.62
(s, 2H), 7.20 (s, 1H), 7.38 (s, 1H).
(±)-tr a n s-2-(3-Meth oxy-4-m eth a n esu lfon yleth oxy-5-io-
d op h en yl)-5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r ofu r a n
(11). To a stirred solution of 9 (4.7 g, 8.87 mmol) in dichlo-
romethane (50 mL) at 0 °C were added methanesulfonyl
chloride (3.05 g, 26.6 mmol) and triethylamine (2.69 g, 26.60
mmol). The reaction was stirred at 0 °C for 2 h and room
temperature overnight. The solvent was evaporated, and the
residue was purified by flash column chromatography (silica
gel, 1:1 hexane/ethyl acetate) to yield 11 as an oil (4.17 g,
77%): 1H NMR δ 1.98 (m, 2H), 2.45 (m, 2H), 3.14 (s, 3H), 3.82
(s, 3H), 3.88 (s, 9H), 4.23 (t, J ) 4.5 Hz, 2H), 4.60 (t, J ) 4.5
Hz, 2H), 5.18 (m, 2H), 6.60 (s, 2H), 6.92 (s, 1H), 7.38 (s, 1H).
IC50
ED50
T1/2
human whole blood
(LTB4)
7.8 µM
RBL (5-LO)
100 nM
10 nM
PAF receptor binding
(3H-PAF)
PAF-induced mouse
hemoconcentration
arachidonic acid-induced
mouse ear edema
TPA-induced mouse ear
edema (edema)a
2.2 mg/kg
30 min
1.8 mg/kg
269 µg/ear (acute)
552 µg/ear (chronic)
299 µg/ear (acute)
TPA-induced mouse ear
edema (MPO)b
580 µg/ear (chronic)
a
Acute TPA-induced ear edema in mice was determined by
topically applying TPA to the ears of mice. Mice were sacrificed
after 6 h and the ear punch biopsies were weighed. Chronic TPA-
induced ear edema in mice was determined by topically applying
TPA once a day every 2 days for a total of 10 days. Compound 40
was topically administered twice daily on the last 3 days of the
experiment. Mice were then sacrificed and the ear punch biopsies
were weighed. b Biopsies were homogenized and MPO content was
determined via spectrophotometric assay.24
(±)-tr a n s-2-[3-Meth oxy-4-(4-ch lor op h en ylth ioeth oxy)-
5-n itr op h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tetr a h yd r ofu -
r a n (12). To a solution of 10 (50.0 mg, 0.095 mmol) in 5 mL
of ethanol were added 4-chlorothiophenol (41.2 mg, 0.285
mmol) and triethylamine (28.7 mg, 0.285 mmol). The reaction
was refluxed for 16 h, quenched with water, and extracted with
ethyl acetate. The organic layer was washed with water and
brine, dried over MgSO4, filtered, and evaporated to yield an
oil which was purified by flash column chromatography (silica
gel, 3:1 hexane/ethyl acetate) to give 12 as an oil (51 mg,
93%): 1H NMR δ 2.00 (m, 2H), 2.49 (m, 2H), 3.31 (t, J ) 7.2
Hz, 2H), 3.85 (s, 3H), 3.89 (s, 9H), 4.25 (t, J ) 7.2 Hz, 2H),
5.20 (m, 2H), 6.61 (s, 2H), 7.16 (s, 1H), 7.26 (d, J ) 8.5 Hz,
2H), 7.32 (s, 1H), 7.34 (d, J ) 8.5 Hz, 2H).
(±)-tr a n s-2-[3-Met h oxy-4-(3,4-d ich lor op h en ylt h ioet -
h oxy)-5-n itr op h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tetr a h y-
d r ofu r a n (13). In a similar manner as for 12 but using 3,4-
dichlorothiophenol (51.0 mg, 0.285 mmol) in place of
4-chlorothiophenol, 10 (50.0 mg, 0.095 mmol) was converted
to 13 as an oil (52.6 mg, 91%): 1H NMR δ 2.00 (m, 2H), 2.50
(m, 2H), 3.33 (t, J ) 7.1 Hz, 2H), 3.84 (s, 3H), 3.89 (s, 6H),
3.91 (s, 3H), 4.27 (t, J ) 7.1 Hz, 2H), 5.22 (m, 2H), 6.61 (s,
2H), 7.17 (s, 1H), 7.24 (m, 1H), 7.36 (m, 2H), 7.47 (s, 1H).
F igu r e 2. Comparison of compound 40 with a PAF receptor
antagonist (BN 50739), a 5-LO inhibitor (zileuton) and the
combination in arachidonic acid-induced mouse ear edema
model. Arachidonic acid-induced ear edema in mice was
determined by measuring the ear weight following the topical
application of arachidonic acid 15 min after intravenous
administration of compound.
(±)-tr a n s-2-(3-Meth oxy-4-h ydr oxyeth oxy-5-n itr oph en yl)-
5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r ofu r a n (8). To a
stirred solution of 6 (8.0 g, 17.1 mmol) in chloroform (80 mL)
at 0 °C was added dropwise trifluoroacetic acid (7.81 g, 68.5
mmol) in chloroform (80 mL) over 30 min. The solution was
stirred at 0 °C for 2 h and then at room temperature for 1 h.
The reaction was diluted with dichloromethane, washed with
10% NaOH solution, water, and saturated NaCl solution, dried
over MgSO4, filtered, and evaporated in vacuo to an oil which
was a cis and trans mixture. The trans isomer 8 was isolated
as a foam by flash column chromatography (silica gel, 1:1
hexane/ethyl acetate) (1.64 g, 21%) as the faster eluting
isomer: 1H NMR δ 2.00 (m, 2H), 2.51 (m, 2H), 3.85 (s, 3H),
3.89 (s, 6H), 3.90 (m, 2H), 3.95 (s, 3H), 4.31 (t, J ) 4.5 Hz,
2H), 5.23 (m, 2H), 6.62 (s, 2H), 7.21 (s, 1H), 7.43 (s, 1H).
(±)-tr a n s-2-(3-Meth oxy-4-h ydr oxyeth oxy-5-iodoph en yl)-
5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r ofu r a n (9). To a
stirred solution of 7 (11.8 g, 21.5 mmol) in chloroform (100
(()-tr a n s-2-[3-Meth oxy-4-(4-br om op h en ylth ioeth oxy)-
5-n it r op h en yl]-5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r o-
fu r a n (14). In a similar manner as for 12 but using 4-bro-
mothiophenol (594.4 mg, 3.144 mmol) in place of 4-chlo-
rothiophenol, 10 (552.1 mg, 1.048 mmol) was converted to 14
as an oil (609.9 mg, 94%): 1H NMR δ 2.00 (m, 2H), 2.50 (m,
2H), 3.32 (t, J ) 7.1 Hz, 2H), 3.86 (s, 3H), 3.90 (s, 9H), 4.25 (t,
J ) 7.1 Hz, 2H), 5.21 (m, 2H), 6.61 (s, 2H), 7.15 (s, 1H), 7.27
(d, J ) 8.2 Hz, 2H), 7.35 (s, 1H), 7.41 (d, J ) 8.2 Hz, 2H).
(()-tr a n s-2-[3-Meth oxy-4-(2-br om op h en ylth ioeth oxy)-
5-n itr op h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tetr a h yd r ofu -
r a n (15). In a similar manner as for 12 but using 2-bo-

1976 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Cai et al.
mothiophenol (53.8 mg, 0.285 mmol) in place of
4-chlorothiophenol, 10 (50.0 mg, 0.095 mmol) was converted
to 15 as an oil (48 mg, 82%): 1H NMR δ 2.00 (m, 2H), 2.50 (m,
2H), 3.39 (t, J ) 7.4 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 6H), 3.90 (s,
3H), 4.32 (t, J ) 7.4 Hz, 2H), 5.22 (m, 2H), 6.62 (s, 2H), 7.04
(m, 1H), 7.16 (s, 1H), 7.31 (m, 1H), 7.36 (s, 1H), 7.41 (d, J )
8.0 Hz, 1H), 7.55(d, J ) 8.0 Hz, 1H).
(()-tr a n s-2-[3-Meth oxy-4-(3-br om op h en ylth ioeth oxy)-
5-n itr op h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tetr a h yd r ofu -
r a n (16). In a similar manner as for 12 but using 3-bro-
mothiophenol (53.8 mg, 0.285 mmol) in place of
4-chlorothiophenol, 10 (50.0 mg, 0.095 mmol) was converted
to 16 as an oil (56 mg, 95%): 1H NMR δ 2.00 (m, 2H), 2.50 (m,
2H), 3.34 (t, J ) 7.1 Hz, 2H), 3.85 (s, 3H), 3.89 (s, 6H), 3.90 (s,
3H), 4.28 (t, J ) 7.1 Hz, 2H), 5.21 (m, 2H), 6.62 (s, 2H), 7.16
(m, 2H), 7.33 (m, 3H), 7.52 (s, 1H).
(()-tr a n s-2-[3-Meth oxy-4-(3-br om op h en ylth ioeth oxy)-
5-a m in op h en yl]-5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r o-
fu r a n (23). Following the same procedure as for 19, 16 (56.0
mg, 0.090 mmol) was converted to 23 as an oil (48 mg, 90%):
1H NMR δ 1.97 (m, 2H), 2.43 (m, 2H), 3.28 (t, J ) 6.4 Hz, 2H),
3.83 (s, 3H), 3.88 (s, 9H), 4.16 (t, J ) 6.4 Hz, 2H), 5.13 (m,
2H), 6.38 (d, J ) 1.8 Hz, 1H), 6.44 (d, J ) 1.8 Hz, 1H), 6.63 (s,
2H), 7.16 (t, J ) 8.0 Hz, 1H), 7.29 (m, 2H), 7.51 (s, 1H).
(()-tr a n s-2-[3-Meth oxy-4-(2,3,5,6-tetr a flu or op h en ylth -
ioeth oxy)-5-a m in op h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tet-
r a h yd r ofu r a n (24). Following the same procedure as for 19,
17 (50.0 mg, 0.082 mmol) was converted to 24 as an oil (33
mg, 69.3%): 1H NMR δ 1.97 (m, 2H), 2.43 (m, 2H), 3.30 (t, J
) 6.3 Hz, 2H), 3.81 (s, 3H), 3.84 (s, 3H), 3.88 (s, 6H), 4.11 (t,
J ) 6.3 Hz, 2H), 5.13 (m, 2H), 6.36 (s, 1H), 6.42 (s, 1H), 6.62
(s, 2H), 7.04 (m, 1H).
(()-tr a n s-2-[3-Meth oxy-4-(2,3,5,6-tetr a flu or op h en ylth -
ioeth oxy)-5-n itr op h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tet-
r a h yd r ofu r a n (17). In a similar manner as for 12 but using
2,3,5,6-tetrafluorothiophenol (51.8 mg, 0.285 mmol) in place
of 4-chlorothiophenol, 10 (50.0 mg, 0.095 mmol) was converted
to 17 as an oil (51 mg, 88%): 1H NMR δ 2.00 (m, 2H), 2.50 (m,
2H), 3.37 (t, J ) 7.1 Hz, 2H), 3.86 (s, 6H), 3.90 (s, 6H), 4.27 (t,
J ) 7.1 Hz, 2H), 5.22 (m, 2H), 6.62 (s, 2H), 7.08 (m, 1H), 7.17
(m, 1H), 7.33(m, 1H).
(±)-tr a n s-2-[3-Meth oxy-4-(4-m eth oxyph en ylth ioeth oxy)-
5-n itr op h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tetr a h yd r ofu -
r a n (18). In a similar manner as for 12 but using 4-methoxy-
thiophenol (123.7 mg, 0.882 mmol) in place of 4-chlorothiophe-
nol, 10 (155.0 mg, 0.294 mmol) was converted to 18 as an oil
(135 mg, 91%): 1H NMR δ 2.00 (m, 2H), 2.49 (m, 2H), 3.22 (t,
J ) 7.1 Hz, 2H), 3.80 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 3.89 (s,
6H), 4.22 (t, J ) 7.1 Hz, 2H), 5.20 (m, 2H), 6.61 (s, 2H), 6.87
(d, J ) 8.2 Hz, 2H), 7.14 (s, 1H), 7.34 (s, 1H), 7.41 (d, J ) 8.2
Hz, 2H).
(()-tr a n s-2-[3-Meth oxy-4-(4-ch lor op h en ylth ioeth oxy)-
5-a m in op h en yl]-5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r o-
fu r a n (19). To a stirred solution of 12 (50.0 mg, 0.087 mmol)
in ethanol (3 mL) was added zinc powder (125.1 mg, 1.91
mmol) and calcium chloride (9.65 mg, 0.087 mmol). The
reaction mixture was heated at reflux for 16 h. The reaction
was filtered and the filtrate was diluted with water and
extracted with ethyl acetate. The organic layer was washed
with water, brine, dried over MgSO4, filtered and evaporated
to give 19 as an oil (42 mg, 88.6%): 1H NMR δ 1.98 (m, 2H),
2.44 (m, 2H), 3.25 (t, J ) 6.3 Hz, 2H), 3.82 (s, 3H), 3.84 (s,
3H), 3.88 (s, 6H), 4.14 (t, J ) 6.3 Hz, 2H), 5.15 (m, 2H), 6.38
(s, 1H), 6.43 (s, 1H), 6.63 (s, 2H), 7.25 (d, J ) 8.5 Hz, 2H),
7.34(d, J ) 8.5 Hz, 2H).
(±)-tr a n s-2-[3-Met h oxy-4-(3,4-d ich lor op h en ylt h ioet -
h oxy)-5-am in oph en yl]-5-(3,4,5-tr im eth oxyph en yl)tetr ah y-
d r ofu r a n (20). Following the same procedure as for 19, 13
(52.4 mg, 0.086 mmol) was converted to 20 as an oil (39 mg,
78%): 1H NMR δ 1.97 (m, 2H), 2.43 (m, 2H), 3.26 (t, J ) 6.4
Hz, 2H), 3.83 (s, 3H), 3.85 (s, 3H), 3.88 (s, 6H), 4.15 (t, J ) 6.4
Hz, 2H), 5.14 (m, 2H), 6.37 (d, J ) 1.8 Hz, 1H), 6.43 (d, J )
1.8 Hz, 1H), 6.62 (s, 2H), 7.22 (m, 1H), 7.33 (d, J ) 8.5 Hz,
1H), 7.45 (s, 1H).
(()-tr a n s-2-[3-Meth oxy-4-(4-m eth oxyph en ylth ioeth oxy)-
5-a m in op h en yl]-5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r o-
fu r a n (25). Following the same procedure as for 19, 18 (130.0
mg, 0.228 mmol) was converted to 25 as an oil (116 mg, 94%):
1H NMR δ 1.98 (m, 2H), 2.43 (m, 2H), 3.15 (t, J ) 6.0 Hz, 2H),
3.79 (s, 3H), 3.81 (s, 3H), 3.84 (s, 3H), 3.88 (s, 6H), 4.10 (t, J
) 6.0 Hz, 2H), 5.13 (m, 2H), 6.36 (s, 1H), 6.43 (s, 1H), 6.62 (s,
2H), 6.83 (d, J ) 7.4 Hz, 2H), 7.42 (d, J ) 7.4 Hz, 2H).
(±)-tr a n s-2-[3-Meth oxy-4-(4-ch lor op h en ylth ioeth oxy)-
5 -( N -b u t y l -N -h y d r o x y u r e i d y l ) p h e n y l ] -5 -( 3 , 4 , 5 -
tr im eth oxyp h en yl)tetr a h yd r ofu r a n (26). To a solution of
19 (38.0 mg, 0.070 mmol) in dry dichloromethane (3 mL) was
added triphosgene (6.83 mg, 0.023 mmol) and triethylamine
(8.47 mg, 0.084 mmol). The reaction mixture was heated to
reflux for 2 h and then cooled with an ice bath. To this mixture
was then added n-butylhydroxylamine (18.6 mg, 0.209 mmol).
The reaction mixture was stirred at room temperature over-
night. The solvent was removed and the product was purified
by flash column chromatography (silica gel, 1:1 hexane/ethyl
acetate) to yield 26 a foam (35 mg, 76%): 1H NMR δ 0.93 (t,
J ) 7.2 Hz, 3H), 1.36 (m, 2H), 1.64 (m, 2H), 2.00 (m, 2H), 2.45
(m, 2H), 3.21 (t, J ) 6.4 Hz, 2H), 3.58 (t, J ) 7.2 Hz, 2H), 3.84
(s, 6H), 3.87 (s, 6H), 4.16 (t, J ) 6.4 Hz, 2H), 5.20 (m, 2H),
6.33 (bs, 1H), 6.62 (s, 2H), 6.74 (s, 1H), 7.24 (d, J ) 8.5 Hz,
2H), 7.29 (d, J ) 8.5 Hz, 2H), 7.89 (s, 1H), 8.65 (s, 1H). Anal.
(C33H41O8N2SCl) C, H, N, S.
(±)-tr a n s-2-[3-Met h oxy-4-(3,4-d ich lor op h en ylt h ioet -
h oxy)-5-(N-bu tyl-N-h yd r oxyu r eid yl)p h en yl]-5-(3,4,5-tr i-
m eth oxyp h en yl)tetr a h yd r ofu r a n (27). Following the same
procedure as for 26, 20 (39.0 mg, 0.067 mmol) was converted
to 27 as a foam (40 mg, 85%): 1H NMR δ 0.93 (t, J ) 7.2 Hz,
3H), 1.35 (m, 2H), 1.63 (m, 2H), 1.98 (m, 2H), 2.46 (m, 2H),
3.23 (t, J ) 6.3 Hz, 2H), 3.59 (t, J ) 7.2 Hz, 2H), 3.84 (s, 3H),
3.85 (s, 3H), 3.88 (s, 6H), 4.17 (t, J ) 6.3 Hz, 2H), 5.20 (m,
2H), 6.62 (s, 2H), 6.75 (s, 1H), 7.18 (m, 1H), 7.33 (d, J ) 8.5
Hz, 1H), 7.43 (m, 1H), 7.90 (s, 1H), 8.61 (s, 1H). Anal.
(C33H40O8N2SCl2) C, H, N.
(±)-tr a n s-2-[3-Meth oxy-4-(4-br om op h en ylth ioeth oxy)-
5-(N-b u t yl-N-h yd r oxyu r eid yl)p h en yl]-5-(3,4,5-t r im et h -
oxyp h en yl)tetr a h yd r ofu r a n (28). Following the same pro-
cedure as for 26, 21 (40.0 mg, 0.068 mmol) was converted to
28 as a foam (20.3 mg, 43%): 1H NMR δ 0.91 (t, J ) 7.2 Hz,
3H), 1.34 (m, 2H), 1.60 (m, 2H), 1.98 (m, 2H), 2.43 (m, 2H),
3.20 (t, J ) 6.3 Hz, 2H), 3.56 (t, J ) 7.2 Hz, 2H), 3.83 (s, 6H),
3.87 (s, 6H), 4.14 (t, J ) 6.3 Hz, 2H), 5.20 (m, 2H), 6.61 (s,
2H), 6.72 (s, 1H), 7.20 (d, J ) 8.5 Hz, 2H), 7.38 (d, J ) 8.5 Hz,
2H), 7.88 (s, 1H), 8.61 (s, 1H). Anal. (C33H41O8N2SBr) C, H,
N.
(()-tr a n s-2-[3-Meth oxy-4-(4-br om op h en ylth ioeth oxy)-
5-a m in op h en yl]-5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r o-
fu r a n (21). Following the same procedure as for 19, 14 (194.0
mg, 0.313 mmol) was converted to 21 as a foam (170 mg,
92%): 1H NMR δ_1.98 (m, 2H), 2.45 (m, 2H), 3.27 (t, J ) 6.4
Hz, 2H), 3.83 (s, 3H), 3.85 (s, 3H), 3.88 (s, 6H), 4.12 (t, J ) 6.4
Hz, 2H), 5.15 (m, 2H), 6.38 (s, 1H), 6.44 (s, 1H), 6.64 (s, 2H),
7.25 (d, J ) 8.5 Hz, 2H), 7.35 (d, J ) 8.5 Hz, 2H).
(()-tr a n s-2-[3-Meth oxy-4-(2-br om op h en ylth ioeth oxy)-
5-a m in op h en yl]-5-(3,4,5-t r im et h oxyp h en yl)t et r a h yd r o-
fu r a n (22). Following the same procedure as for 19, 15 (47.8
mg, 0.077 mmol) was converted to 22 as an oil (39 mg,
85.7%): 1H NMR δ 1.98 (m, 2H), 2.44 (m, 2H), 3.30 (m, 2H),
3.82 (s, 3H), 3.84 (s, 3H), 3.88 (s, 6H), 4.20 (m, 2H), 5.14 (m,
2H), 6.37 (s, 1H), 6.43 (s, 1H), 6.63 (s, 2H), 7.20 (m, 1H), 7.29
(m, 1H), 7.40 (m, 1H), 7.55 (m, 1H).
(±)-tr a n s-2-[3-Meth oxy-4-(2-br om op h en ylth ioeth oxy)-
5-(N-b u t yl-N-h yd r oxyu r eid yl)p h en yl]-5-(3,4,5-t r im et h -
oxyp h en yl)tetr a h yd r ofu r a n (29). Following the same pro-
cedure as for 26, 22 (39.0 mg, 0.066 mmol) was converted to
29 as an oil (35 mg, 75%): 1H NMR δ 0.92 (t, J ) 7.1 Hz, 3H),
1.36 (m, 2H), 1.64 (m, 2H), 2.00 (m, 2H), 2.45 (m, 2H), 3.26
(m, 2H), 3.58 (t, J ) 7.1 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H),
3.87 (s, 6H), 4.18 (m, 2H), 5.20 (m, 2H), 6.62 (s, 2H), 6.75 (s,
1H), 7.26 (m, 2H), 7.37 (m, 1H), 7.53 (m, 1H), 7.92 (s, 1H),
8.68 (s, 1H). Anal. (C33H41O8N2SBr) C, H, N.

CMI-392: A Potent Dual 5-Lipoxygenase Inhibitor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1977
(±)-tr a n s-2-[3-Meth oxy-4-(3-br om op h en ylth ioeth oxy)-
5-(N-b u t yl-N-h yd r oxyu r eid yl)p h en yl]-5-(3,4,5-t r im et h -
oxyp h en yl)tetr a h yd r ofu r a n (30). Following the same pro-
cedure as for 26, 23 (48.0 mg, 0.082 mmol) was converted to
30 as an oil (46 mg, 80%): 1H NMR δ 0.91 (t, J ) 7.1 Hz,,3H),
1.35 (m, 2H), 1.61 (m, 2H), 2.00 (m, 2H), 2.46 (m, 2H), 3.22 (t,
J ) 6.3 Hz, 2H), 3.57 (t, J ) 7.1 Hz, 2H), 3.83 (s, 3H), 3.85 (s,
3H), 3.87 (s, 6H), 4.16 (t, J ) 6.3 Hz, 2H), 5.20 (m, 2H), 6.55
(bs, 1H), 6.62 (s, 2H), 6.73 (s, 1H), 7.12 (m, 1H), 7.26 (m, 2H),
7.48 (s, 1H), 7.89 (s, 1H), 8.61 (s, 1H). Anal. (C33H41O8N2-
SBr) C, H, N, S.
(±)-tr a n s-2-[3-Meth oxy-4-(2,3,5,6-tetr a flu or op h en ylth -
ioeth oxy)-5-(N-bu tyl-N-h yd r oxyu r eid yl)p h en yl]-5-(3,4,5-
t r im et h oxyp h en yl)t et r a h yd r ofu r a n (31). Following the
same procedure as for 26, 24 (33.0 mg, 0.057 mmol) was
converted to 31 as an oil (28 mg, 71%): 1H NMR δ 0.95 (t, J
) 7.2 Hz, 2H), 1.38 (m, 2H), 1.62 (m, 2H), 2.00 (m, 2H), 2.46
(m, 2H), 3.29 (t, J ) 6.1 Hz, 2H), 3.61 (t, J ) 7.2 Hz, 2H), 3.84
(s, 6H), 3.88 (s, 6H), 4.18 (t, J ) 6.1 Hz, 2H), 5.20 (m, 2H),
6.62 (s, 2H), 6.74 (s, 1H), 7.06 (m, 1H), 7.91 (s, 1H), 8.63 (s,
1H). Anal. (C33H38O8N2SF4) C, H, N.
(±)-tr a n s-2-[3-Meth oxy-4-(4-m eth oxyph en ylth ioeth oxy)-
5-(N-b u t yl-N-h yd r oxyu r eid yl)p h en yl]-5-(3,4,5-t r im et h -
oxyp h en yl)tetr a h yd r ofu r a n (32). Following the same pro-
cedure as for 26, 25 (31.0 mg, 0.057 mmol) was converted to
32 as a foam (25.8 mg, 70%): 1H NMR δ 0.93 (t, J ) 7.3 Hz,
3H), 1.37 (m, 2H), 1.63 (m, 2H), 2.00 (m, 2H), 2.45 (m, 2H),
3.11 (t, J ) 6.1 Hz, 2H), 3.60 (t, J ) 7.3 Hz, 2H), 3.79 (s, 3H),
3.81 (s, 3H), 3.83 (s, 3H), 3.88 (s, 6H), 4.14 (t, J ) 6.1 Hz, 2H),
5.20 (m, 2H), 6.62 (s, 2H), 6.73 (s, 1H), 6.83 (d, J ) 8.8 Hz,
2H), 7.37 (d, J ) 8.8 Hz, 2H), 7.91 (s, 1H), 8.75 (s, 1H). Anal.
(C34H44O9N2S) C, H, N.
(±)-t r a n s -2-[3-M e t h o x y -4-(4-b r o m o p h e n y l s u l fo -
n ylet h oxy)-5-(N-b u t yl-N-h yd r oxyu r eid yl)]-5-(3,4,5-t r i-
m eth oxyp h en yl)tetr a h yd r ofu r a n (33). To a stirred solu-
tion of 28 (10.0 mg, 0.014 mmol) in acetonitrile (1 mL) was
added magnesium monoperoxyphthalic acid (MMPP) in water
(0.1 mL). The reaction was stirred at room temperature for 2
h, diluted with water, and extracted with ethyl acetate. The
extract was washed with water and brine. The product was
separated by flash column chromatography (silica gel, 1:1
hexane/ethyl acetate) to give 33 as an oil (5.6 mg, 53%): 1H
NMR δ 0.95 (t, J ) 7.4 Hz, 3H), 1.40 (m, 2H), 1.68 (m, 2H),
2.00 (m, 2H), 2.47 (m, 2H), 3.53 (t, J ) 5.0 Hz, 2H), 3.64 (t, J
) 7.4 Hz, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 3.89 (s, 6H), 4.43 (t,
J ) 5.0 Hz, 2H), 5.21 (m, 2H), 6.63 (s, 2H), 6.76 (s, 1H), 7.73
(d, J ) 8.7 Hz, 2H), 7.81 (d, J ) 8.7 Hz, 2H), 7.91 (s, 1H), 8.60
(s, 1H). Anal. (C33H41O10N2SBr) C, H, N; C: calcd, 53.73;
found, 53.20.
(±)-t r a n s -2-[3-M e t h o x y -4 -(2 -b r o m o p h e n y l s u l fo -
n yleth oxy)-5-(N-bu tyl-N-h ydr oxyu r eidyl)ph en yl]-5-(3,4,5-
t r im et h oxyp h en yl)t et r a h yd r ofu r a n (34). Following the
same procedure described above for converting 28 to 33, 29
(20.0 mg, 0.028 mmol) was transformed to 34 as a foam (14
mg, 67%): 1H NMR δ 0.95 (t, J ) 7.4 Hz, 3H), 1.40 (m, 2H),
1.68 (m, 2H), 2.01 (m, 2H), 2.47 (m, 2H), 3.54 (t, J ) 4.5 Hz,
2H), 3.65 (t, J ) 7.4 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 3.88 (s,
6H), 4.43 (t, J ) 4.5 Hz, 2H), 5.22 (m, 2H), 6.64 (s, 2H), 6.75
(s, 1H), 7.61 (m, 2H), 7.71 (m, 1H), 7.92 (m, 1H), 7.96 (s, 1H),
8.66 (s, 1H). Anal. (C33H41O10N2SBr) C, H, N.
(±)-tr a n s-2-[3-Meth oxy-4-(2,3,5,6-tetr a flu or op h en ylsu l-
fon ylet h oxy)-5-(N-b u t yl-N-h yd r oxyu r eid yl)p h en yl]-5-
(3,4,5-tr im eth oxyp h en yl)tetr a h yd r ofu r a n (35). Following
the same procedure described above for converting 28 to 33,
31 (38.0 mg, 0.054 mmol) was transformed to 35 as an oil (25
mg, 63%): 1H NMR δ 0.93 (t, J ) 7.4 Hz, 3H), 1.38 (m, 2H),
1.65 (m, 2H), 2.00 (m, 2H), 2.47 (m, 2H), 3.51 (m, 2H), 3.61
(m, 2H), 3.84 (s, 3H), 3.88 (s, 9H), 4.45 (m, 2H), 5.21 (m, 2H),
6.62 (s, 2H), 6.80 (s, 1H), 7.31 (m, 1H), 7.82 (s, 1H), 8.32 (s,
1H). Anal. (C33H38O10N2SF4) C, H, N.
mmol) and triethylamine (0.831 g, 8.22 mmol). The reaction
mixture was heated at reflux for 16 h, and then the solvent
was removed. The residue was purified by flash column
chromatography (silica gel, 3:1 hexane/ethyl acetate) to yield
36 as an oil (2.35 g, 87%): 1H NMR δ 1.96 (m, 2H), 2.45 (m,
2H), 3.35 (t, J ) 7.1 Hz, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 3.88 (s,
6H), 4.11 (t, J ) 7.1 Hz, 2H), 5.17 (m, 2H), 6.61 (s, 2H), 6.92
(s, 1H), 7.26 (d, J ) 8.4 Hz, 2H), 7.33 (d, J ) 8.4 Hz, 2H), 7.35
(s, 1H).
(±)-tr a n s-2-[3-Meth oxy-4-(4-ch lor op h en ylth ioeth oxy)-
5-cya n op h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tetr a h yd r ofu -
r a n (37). A mixture of 36 (2.35 g, 3.58 mmol) and CuCN (0.36
g, 4.30 mmol) in DMF (20 mL) was heated with stirring at
140 °C for 16 h. The reaction was cooled, diluted with water,
and extracted with ethyl acetate. The extract was washed
with water and saturated NaCl solution, dried over MgSO4,
filtered, and evaporated. The title compound was purified by
flash column chromatography (silica gel, 2:1 hexane/ethyl
acetate) as an oil (1.79 g, 90.0%): 1H NMR δ 1.99 (m, 2H),
2.49 (m, 2H), 3.36 (t, J ) 7.2 Hz, 2H), 3.82 (s, 3H), 3.84 (s,
3H), 3.89 (s, 6H), 4.28 (t, J ) 7.2 Hz, 2H), 5.20 (m, 2H), 6.61
(s, 2H), 7.16 (s, 2H), 7.27 (d, J ) 8.1 Hz, 2H), 7.32 (d, J ) 8.1
Hz, 2H).
(±)-tr a n s-2-[3-Meth oxy-4-(4-ch lor op h en ylth ioeth oxy)-
5-a m in om et h ylp h en yl]-5-(3,4,5-t r im et h oxyp h en yl)t et -
r a h yd r ofu r a n (38). To a solution of 37 (300.0 mg, 0.54 mmol)
in THF (10 mL) were added sodium borohydride (36.8 mg, 0.97
mmol) and boron trifluoride etherate (191.8 mg, 1.35 mmol)
dropwise. The reaction mixture was heated at reflux for 1 h
and cooled with an ice-water bath, and then a few drops of
10% HCl was added. The reaction mixture was poured into
10% K2CO3 and extracted with ethyl acetate. The organic
layer was washed with water and saturated NaCl solution,
dried over MgSO4, filtered, and evaporated. The title com-
pound was purified by flash column chromatography (silica
gel, 93:7 CH2Cl2/MeOH) as a gum (64 mg, 21.2%): 1H NMR δ
1.98 (m, 2H), 2.46 (m, 2H), 2.50 (m, 2H), 3.28 (t, J ) 6.6 Hz,
2H), 3.83 (s, 3 H), 3.84 (s, 3H), 3.88 (s, 6H), 3.90 (m, 2H), 4.17
(t, J ) 6.6 Hz, 2H), 5.18 (m, 2H), 6.62 (s, 2H), 6.91 (s, 2H),
7.25 (d, J ) 8.5 Hz, 2H), 7.32 (d, J ) 8.5 Hz, 2H).
(+)-tr a n s-2-[3-Meth oxy-4-(4-ch lor op h en ylth ioeth oxy)-
5-(N-bu tyl-N-h yd r oxyu r eid yl)m eth ylp h en yl]-5-(3,4,5-tr i-
m eth oxyp h en yl)tetr a h yd r ofu r a n (39). To a stirred solu-
tion of 38 (390.0 mg, 0.70 mmol) in dry dichloromethane (30
mL) were added triphosgene (68.8 mg, 0.23 mmol) and
triethylamine (71.7 mg, 0.70 mmol). The reaction mixture was
heated at reflux for 2 h and then cooled to room temperature.
To this solution was then added n-butylhydroxylamine (187.6
mg, 2.11 mmol), with further stirring at room temperature
overnight. The reaction was quenched with water and ex-
tracted with dichloromethane. The organic layer was washed
with water and saturated NaCl solution, dried over MgSO4,
filtered, and evaporated in vacuo. The product 39 was purified
by flash column chromatography (silica gel, 1:1 hexane/ethyl
acetate) to give a solid (151 mg, 32%): mp 55-57 °C; 1H NMR
δ 0.92 (t, J ) 7.4 Hz, 3H), 1.33 (m, 2H), 1.55 (m, 2H), 1.98 (m,
2H), 2.45 (m, 2H), 3.29 (t, J ) 6.6 Hz, 2H), 3.50 (t, J ) 7.4 Hz,
2H), 3.84 (s, 6H), 3.88 (s, 6H), 4.17 (t, J ) 6.6 Hz, 2H), 4.43 (d,
J ) 5.8 Hz, 2H), 5.18 (m, 2H), 6.41 (t, J ) 5.8 Hz, 1H), 6.62 (s,
2H), 6.92 (s, 2H), 7.26 (d, J ) 8.6 Hz, 2H), 7.33 (d, J ) 8.6 Hz,
2H). Anal. (C34H43O8N2SCl) C, H, N, S.
(±)-tr a n s-2-[3-Meth oxy-4-(4-ch lor op h en ylth ioeth oxy)-
5-(N-m et h yl-N-h yd r oxyu r eid yl)m et h ylp h en yl]-5-(3,4,5-
tr im eth oxyp h en yl)tetr a h yd r ofu r a n (40). To a stirred
solution of 38 (54.0 mg, 0.10 mmol) in dry dichloromethane (4
mL) were added triphosgene (9.46 mg, 0.03 mmol) and
triethylamine (9.77 mg, 0.10 mmol). The reaction mixture was
heated at reflux for 2 h and then cooled to room temperature.
To this mixture were then added triethylamine (35.2 mg, 0.35
mmol) and methylhydroxylamine hydrochloride (24.2 mg, 0.29
mmol). The reaction was stirred at room temperature over-
night. The reaction mixture was quenched with water and
extracted with dichloromethane. The organic layer was
washed with water and saturated NaCl solution, dried over
(±)-tr a n s-2-[3-Meth oxy-4-(4-ch lor op h en ylth ioeth oxy)-
5-iod op h en yl]-5-(3,4,5-tr im eth oxyp h en yl)tetr a h yd r ofu -
r a n (36). To a stirred solution of 11 (2.5 g, 4.11 mmol) in
ethanol (50 mL) was added 4-chlorothiophenol (1.19 g, 8.22

1978 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Cai et al.
MgSO4, filtered, and evaporated. The product 40 was purified
by flash column chromatography (silica gel, 1:1 hexane/ethyl
acetate) (49 mg, 80%) to give a solid: mp 68-70 °C; 1H NMR
δ 1.98 (m, 2H), 2.44 (m, 2H), 3.08 (s, 3H), 3.27 (t, J ) 6.6 Hz,
2H), 3.82 (s, 3H), 3.83 (s, 3H), 3.87 (s, 6H), 4.15 (t, J ) 6.6 Hz,
2H), 4.40 (d, J ) 5.7 Hz, 2H), 5.17 (m, 2H), 6.41 (m, 1H), 6.61
(s, 2H), 6.77 (bs, 1H), 6.90 (s, 2H), 7.25 (d, J ) 8.7 Hz, 2H),
7.31 (d, J ) 8.7 Hz, 2H); 13C NMR δ 33.9, 35.6, 35.7, 39.1,
39.8, 55.8, 56.2, 60.9, 70.9, 81.2, 81.6, 102.5, 109.1, 118.7, 129.1,
130.8, 132.2, 139.2, 139.6, 152.1, 153.5, 161.8. Anal.
(C31H37O8N2SCl) C, H, N, S.
(Cayman Chemical). The percent inhibition for each sample
was calculated and an IC50 value obtained via regression
analysis.
P AF -In d u ced Hem ocon cen tr a tion in Mice. PAF was
dissolved in 0.25% BSA in 0.9% NaCl. Except for dose-
response studies, 10 µg (10 mL/kg) was injected into the tail
vein. All test compounds were dissolved in 0.5% DMSO saline
solution and intravenously injected at 3 mg (10 mL/kg) body
weight at various times prior to PAF challenge. Blood (30-
50 µL) was collected by cutting the tail end into a heparinized
microhematocrit tube (O.D. 1.50 mm) 15 min after PAF
administration. The percent inhibition of PAF-induced hemo-
concentration for each experimental assay was calculated with
respect to the hematocrit observed in the vehicle control.
Ar ach idon ic Acid-In du ced Ear Edem a in Mice. Arachi-
donic acid was applied to both ears of mice in 0.025 mL of
freshly prepared vehicle (acetone/pyridine/water (97:2:1 v/v/
v) and dried under a Sun-Lite Hitensity bulb. Except for
dose-response studies, 0.5 mg of arachidonic acid was used
for all applications. All test compounds were dissolved in 0.5%
DMSO saline solution and intravenously injected at 3 mg/kg
body weight 15 min prior to arachidonic acid treatment.
Animals were sacrificed by cervical dislocation at 1 h after
topical application of arachidonic acid. A 7-mm-diameter disk
of tissue was removed from each ear by means of a metal
punch. Edema was measured by the average wet weight of
both ear tissue.
Acu te TP A-In d u ced Ea r Ed em a in Mice. Eight mice per
group were administered 10 µL of TPA solution (acetone) or
vehicle (acetone) with or without drug on both surfaces of each
ear for each animal. All animals within the group were
sacrificed after 6 h. Tissues were taken with a biopsy punch
and weighed. The left ear was then placed in a fixative
solution for later histological analysis. The right ear was
placed into a 5 mL centrifuge tube and stored at -80 °C for
later analysis of MPO activity. Experimental treatment group
responses were compared to the maximal control for inhibition
of edema by analysis of ear mass, dermal histology, and MPO
production.
Ch r on ic TP A-In d u ced Ea r Ed em a in Mice. Eight mice
per group were administered 10 µL of TPA solution (acetone)
or vehicle (acetone) with or without drug on both surfaces of
each ear for each animal. All animals within the group were
dosed with TPA once a day every 2 days for a total of 10 days
in order to induce the chronic inflammatory response. Drugs
were administered twice daily on the last 3 days of the
experiment. Animals were sacrificed by CO2 asphyxiation.
Tissues were taken with a biopsy punch and weighed. The
left ear was then placed in a fixative solution for histological
analysis. The right ear was stored at -80 °C for later analysis
of MPO activity. Representative ear samples from each group
were subjected to histological evaluation. Experimental treat-
ment group responses were compared to the maximal control
for inhibition of edema by analysis of ear mass, dermal
histology, and MPO production.
P AF Recep tor Bin d in g Assa y. CHO cells expressing the
human PAF receptor were grown to confluence (2 × 106/mL)
in spinner flasks, harvested, and washed with 20 nM Tris, 5
mM EDTA, 0.15 M NaCl, pH 7.4. Cells were resuspended in
homogenization buffer (20 mM Tris pH 7.4, 5 mM EDTA, 225
mM sucrose, 1 mM PMSF) at 1 × 108/mL and lysed by
sonication. Five milliliters of extract was layered over a
sucrose gradient containing 5 mL each of 0.25, 1.03, and 1.5
M sucrose in homogenization buffer and centrifuged (48000g,
2 h, 4 °C). The membrane fractions located at the interface of
the 1.5 and 1.03 M sucrose layers and the membrane pellet at
the bottom of the tube were pooled; the protein concentration
was determined by solubilization in 1% SDS and quantitation
using the BCA reagent (Pierce).
The membrane preparation, compound, and 3 nM [3H]PAF
in 0.25 mL of binding buffer (10 mM Tris pH 7.0, 0.25% BSA,
30 mM MgCl2) were incubated (3 h, 4 °C) in a microtiter plate.
The reaction was then transferred to glass fiber plate filters
using a Packard Filtermate 196 plate harvester. Filters were
washed three times with ice cold 10 mM Tris pH 7.0, 0.25%
BSA. Packard Microscint-20 scintillation fluid (25 µL) was
added to each well, and the plate was counted using a Packard
Top Count. Specific binding was determined by subtracting
the value obtained in the presence of excess unlabeled PAF
from that obtained in the absence of unlabeled PAF. Percent
inhibition at each dose of compound was determined from the
decrease in specific binding, and IC50 value was calculated.
5-LO Assa y in RBL Cell Extr a cts. RBL-2H3 cells were
grown to confluence according to literature protocols. Cells
were harvested and washed twice in buffer. Cells were
suspended at 2 × 107/mL in 10 mM BES, 10 mM PIPES, 1
mM EDTA, pH 6.8 buffer and sonicated. The cell lysate was
centrifuged (20000g, 20 min, 4 °C); the supernatant was
removed and stored in aliquots at -70 °C.
5-LO activity in cell lysate was determined as follows: 0.1
mL reactions consisting of 10 mM BES, 10 mM PIPES, 0.1 M
NaCl, 1 mM EDTA, 0.7 mM CaCl2, pH 6.8, test compound (in
DMSO), and an amount of cell lysate that will convert ∼15%
of [14C]AA substrate mix to oxygenated products were incu-
bated (20 min, room temperature). A substrate mix containing
[14C]AA was added and incubated further (5 min, 37 °C).
The reaction was terminated by adding 0.2 mL of an organic
extraction solution containing triphenylphosphine, followed by
microcentrifugation. The organic phase (50 µL) was spotted
onto silica gel TLC plates. The plates were developed in ethyl
ether/acetic acid (100:0.1) (25 min, room temperature). Plates
were exposed to film for 36 h. The film was developed and
scanned using a densitometer, and the peak areas of AA and
its products were calculated. Percent inhibition was deter-
mined from the amount of [14C]AA converted into oxygenated
products in samples containing test compound relative to that
of control samples (no test compound), and an IC50 value was
obtained via regression analysis.
Ack n ow led gm en t. The authors thank Dr. Richard
Fisher, Professor Robert Stevenson, and Dr. Donna M.
Wypij for editorial assistance.
Refer en ces
(1) Musser, J . H.; Kreft, A. F. 5-Lipoxygenase: Properties, Phar-
macology and the Quinolinyl(bridged)aryl Class of Inhibitors.
J . Med. Chem. 1992, 35, 2501-2524.
(2) Lewis, R. A.; Austen, K. F.; Soberman, R. J . Leukotrienes and
Other Products of the 5-Lipoxygenase pathway. N. Engl. J . Med.
1990, 323, 645-655.
LTB4 P r od u ction fr om Hu m a n Wh ole Blood . Human
blood was drawn into heparinized blood collection tubes and
aliquoted in 1 mL portions into 1.5 mL microfuge tubes. Five
microliters of test compound (at selected concentration in
DMSO) was added to the blood sample and incubated for 15
min at 37 °C. Calcium ionophore (A23187 in DMSO, 50 µM
final concentration) and the samples were incubated (30 min,
37 °C). The samples were centrifuged (1100g, 10 min, 4 °C),
and the supernatant was assayed for LTB4 using an EIA kit
(3) Henderson, W. R. The Role of Leukotrienes in inflammation.
Ann. Intern. Med. 1994, 121, 684-697.
(4) Ford-Hutchinson, A. W.; Bray, M. A.; Doig, M. V.; Shipley, M.
E.; Smith, M. J . H. Leukotriene B4, a Potent Chemokinetic and
Aggregating Substance Released from Polymorphonuclear Leu-
kocytes. Nature 1980, 286, 264-265.
(5) Orange, R. P.; Austen, K. F. Slow Reacting Substance of
Anaphylaxis. Adv. Immunol. 1969, 10, 105-144.

CMI-392: A Potent Dual 5-Lipoxygenase Inhibitor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1979
(6) Snyder, F. Chemical and Biological Aspects of Platelet Activating
Factor: A Novel Class of Acetylated Ether-Linked Chloline-
Phospholipids. Med. Res. Rev. 1985, 5, 107-140.
(7) Shen, T. Y.; Hwang S.-B.; Doebber, T. W.; Robbins, J . C. The
Chemical and Biological Properties of PAF Agonists, Antagonists
and Biosynthetic Inhibitors. In Platelet-Activating Factor and
Related Lipid Mediator; Snyder, F., Ed.; Plenum Press: New
York, 1987; pp 152-190.
(8) Hwang, S.-B. Specific Receptors of Platelet-Activating Factor,
Receptor Heterogeneity, and Signal Transduction Mechanisms.
J . Lipid Mediators 1990, 2, 123-158.
(9) Hosford, D.; Braquet, P. Antagonists of Platelet-Activating
Factor: Chemistry, Pharmacology and Clinical Applications. In
Progress in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds.;
Elsevier Science Publisher: Amsterdam, 1990; Vol. 27, pp 325-
380.
(10) Hussoin, M. S.; Yeh, C. G. The Design of Dual-Acting Compounds
with PAF Receptor Antagonistic and 5-Lipoxygenase Inhibitory
Activities. Drug Future 1996, 21, 933-944.
(11) Summers, J . B.; Davidsen, S. K.; Sheppard, G. S. Platelet
Activating Factor Antagonists. Curr. Pharm. Des. 1995, 1, 161-
190.
(12) Batt, D. G. 5-Lipoxygenase Inhibitors and Their Anti-inflam-
matory Activities. Prog. Med. Chem. 1992, 29, 1-63.
(13) Goldstein, D. M.; Shen, T. Y. Dual Inhibitors of Platelet-
Activating Factor and 5-Lipoxygenase, 2,4-Diaryl-1,3-Dithi-
olanes. Med. Chem. Res. 1992, 2, 443.
(14) Cai, X.; Hussoin, M. S.; Killian, D. B.; Scannell, R.; Yaeger, D.;
Eckman, J .; Hwang, S.-B.; Garahan, L.-L.; Qian, C.; Yeh, G.;
Ip, S. Synthesis of Substituted-Hydroxyureidyl diaryltetrahy-
drofurans, a Potent Class of Dual Inhibitors of 5-Lipoxygenase
(5-LO) and Platelet-Activating Factor (PAF), 207th ACS Meeting
(March 13-17, San Diego), 1994, MEDI 123.
(15) Hussoin, M. S.; Cai, X.; Scannell, R.; Yaeger, D.; Eckman, J .;
Hwang, S.-B.; Garahan L.-L.; Qian, C.; Yeh, G.; Ip, S. Platelet
Activating Factor and 5- Lipoxygenase Inhibitory Activity of
(CMI-206) Hydroxyureidyl Tetrahydrofuran/Tetrahydrothiophene,
208th ACS Meeting (Aug. 21-25, Washington, DC), 1994, MEDI
126.
(16) Hussion, M. S.; Cai, X.; Scannell, R.; Yaeger, D.; Killian, D. B.;
Eckman, J .; Hwang, S.; Garahan, L.-L.; Qian, C.; Yeh, G.; Ip, S.
CMI-206: A potent Dual Platelet Activating Factor antagonist
and 5-Lipoxygenase Inhibitor. Bioorg. Med. Chem. Lett. 1995,
5, 643-8.
(17) Hussoin, M. S.; Biftu, T.; Cai, X.; Scannell, R.; Grewal G.; Young
M.; Yaeger, D.; Killian, D. B.; Wypij D.; Lobell R.; Eckman, J .;
Garahan, L.-L.; Qian, C.; Yeh, G. Synthesis and Biological
Activity of a Potent Dual-Acting Platelet Activating Factor and
5-Lipoxygenase Inhibitor. 211th ACS Meeting (March 24-28,
New Orleans), 1996, MEDI 205.
(18) Girotra, N.N.; Biftu, T.; Ponpipom, M. M.; Acton, J . J .; Alberts,
A. W.; Bach, T. N.; Ball, R.G.; Bugianeasi, R. L.; Parson, W. H.;
Chabala, J .C.; Davies, P.; Doebber, T.W.; Doherty, J .; Graham,
D.W.; Hwang, S. B.; Kuo, C. H.; Lam, M.-H.; Luell, S.; MacIntyre,
D.E.; Meurer, R.; Roberts, C.D.; Sahoo, S. P.; Wu, M. S.
Development, Synthesis, and Biological Evaluation of (-)-trans-
(2S, 5S)-2-[3-[(2-Oxopropyl)sulfonyl]-4-n-propoxy-5-(3-hydrox-
ypropoxy)-phenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran,
a Potent Orally Active Platelet-Activating Factor (PAF) Antago-
nist and Its Water-Soluble Prodrug Phosphate Ester. J . Med.
Chem. 1992, 35, 3474-3482.
(19) Sirois, P.; Borgeat, P.; Lauziere, M.; Dube, L.; Rubin, P.;
Kesterson, J . Effect of Zileuton (A-64077) on the 5-Lipoxygenase
Activity of Human Whole Blood ex Vivo. Agents Action 1991,
34, 117-120.
(20) Carter, G. W.; Young, P. R.; Albert, D. H.; Bouska, J .; Dyer, R.;
Bell, R. L.; Summers, J . B.; Brooks, D. W. 5-Lipoxygenase
Inhibitory Action of Zileuton. J . Pharmacol. Exp. Ther. 1991 256,
929-937.
(21) Inarrea, P.; Alonso, F.; Sanchez-Crespo, M. Platelet-Activating
Factor: an Effector Substance of the Vasopermeability Changes
Induced by the Infusion of Immune Aggregates in the Mouse.
Immunopharmacology 1983, 6, 7-14.
(22) Carlson, R. P.; O’Neill-Davis, L.; Chang, J .; Lewis, A. J . Modula-
tion of Mouse Ear Edema by Cyclooxygenase and Lipoxygenase
Inhibitors and other Pharmacologic Agents. Agents Action 1985,
17, 197-204.
(23) Opas, E. E.; Bonney, R. J .; Humes, J . L. Prostaglandin and
Leukotriene Synthesis in Mouse Ears Inflamed by Arachidonic
Acid. J . Invest. Dermatol. 1985, 84, 253-256.
(24) Bradley, P. P.; Priebat, D. A.; Christensen, R. D.; Rothetein, G.
Measurement of Cutaneous Inflammation: Estimation of Neu-
trophil Content with an Enzyme Marker. J . Invest. Dermatol.
1982, 78, 206-209.
(25) Obtained from Societe de Conseils de Recherches et d’Applications
Scientifiques.
J M980046R