Discovery of low nanomolar non-hydroxamate inhibitors of tumor necrosis factor-α converting enzyme (TACE)

Article abstract of DOI:10.1016/j.bmcl.2006.09.048

Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-α converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC₅₀

Full text of DOI:10.1016/j.bmcl.2006.09.048

Bioorganic & Medicinal Chemistry Letters 17 (2007) 266–271
Discovery of low nanomolar non-hydroxamate inhibitors
of tumor necrosis factor-a converting enzyme (TACE)
James J.-W. Duan,a,* Lihua Chen,a Zhonghui Lu,a Bin Jiang,a Naoyuki Asakawa,a
James E. Sheppeck, II,a Rui-Qin Liu,b Maryanne B. Covington,b William Pitts,a
Soong-Hoon Kima and Carl P. Deciccoa
aDepartment of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
bDepartment of Discovery Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
Received 26 July 2006; revised 14 September 2006; accepted 18 September 2006
Available online 5 October 2006
Abstract—Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-a
converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC50 of 2 nM in
a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxa-
mate-based inhibitors of TACE with single digit nanomolar potency.
Ó 2006 Elsevier Ltd. All rights reserved.
Tumor necrosis factor-a (TNFa) converting enzyme
(TACE) and matrix metalloproteinases (MMPs) are
both zinc endopeptidases. Most of the inhibitors of
TACE and MMPs were derived using hydroxamic acid
as zinc-binding group.1 Because hydroxamic acids are
often poorly absorbed and are prone to metabolic deg-
radation and glucuronidation, there has been consider-
able interest in discovering alternative groups to the
hydroxamic acid. While significant progress has been
made toward non-hydroxamate MMP inhibitors,2 the
TACE inhibitor arena still relies mostly on the hydroxa-
mic acid group.1a
optimized for TACE in our laboratories.5 Preliminary
SAR study led to inhibitors with potency around
100 nM and good selectivity against several MMPs.
While encouraging for non-hydroxamate TACE inhibi-
tors, the potency level was 1–2 orders of magnitude
weaker than most of the optimized hydroxamate inhib-
itors. Furthermore, the series was inactive in cellular as-
says. Continuing the SAR study, we investigated the
effect of different linkers between the pyrimidinetrione
and 4-(2-methylquinolin-4-ylmethoxy)phenyl groups
(linker –A– in compound 2), including elongation with
alkylene, alkenylene, ether, and amide. This letter dis-
closes the results from this study as well as attempts to
improve cell activity.
As a part of the effort to discover new inhibitors of
TNFa for the treatment of rheumatoid arthritis and
other inflammatory diseases, we reported a series of
TACE inhibitors using a pyrimidine-2,4,6-trione in
place of the commonly used hydroxamic acid.3 Even
though pyrimidinetriones were reported by several
groups as MMP inhibitors,4 they had not been used in
TACE inhibitors prior to our publication. We synthe-
sized a 1 lM inhibitor of TACE (1) by combining the
pyrimidinetrione with a 4-(2-methylquinolin-4-ylmeth-
oxy)phenyl group, which was previously designed and
Scheme 1 depicts synthesis of analogues with 3-carbon
linkers between the pyrimidinetrione and the phenyl side
chain. Treatment of 36 with dimethyl methylmalonate
O
HN
O
N
O
N
H
O
1
2
O
R
HN
A
O
Keywords: TACE inhibitor; ADAM-17 inhibitor; Pyrimidinetrione.
*
N
Corresponding author. Tel.: +1 609 252 4199; e-mail: james.
duan@bms.com
O
N
H
O
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.09.048

J. J.-W. Duan et al. / Bioorg. Med. Chem. Lett. 17 (2007) 266–271
267
OTBS
MeO2C
MeO2C
OTBS
MeO2C
MeO2C
CO2H
a
Br
MeO2C
MeO2C
MeO2C
10
4
NH2
3
MeO2C
b-d
R
O
f-h
11
MeO2C
9
N
O
R
MeO2C
MeO2C
MeO2C
HN
O
12
O
O
O
O
HN
5
7
HN
HN
O
O
h,i
O
e
NH
O
N
i
O
O
R
R
HN
HN
HN
13
O
HN
Scheme 2. Reagents and conditions: (a) NaH, allyl bromide, THF; (b)
O3, CH2Cl2, PPh3 (75% for two steps); (c) NaClO2, KH2PO4,
2-methyl-2-butene, t-BuOH, THF, H2O; (d) DPPA, Et3N, BnOH,
benzene, at reflux (79% for two steps); (e) H2, Pd/C, MeOH (100%); (f)
NaH, N-(bromomethyl)phthalimide, DMF (90%); (g) NH2NH2,
MeOH, at reflux (53%); (h) 4-(2-methylquinolin-4-ylmethoxy)benzoyl
chloride, NaHCO3, CH2Cl2, H2O (94%); (i) urea, Mg, MeOH, at reflux
(21%).
O
6
O
O
8
N
R =
O
Scheme 1. Reagents and conditions: (a) NaH, dimethyl methylmalo-
nate, THF (52%); (b) H2, Pd/C, EtOAc, MeOH (88%); (c) TBAF, THF
(94%); (d) 4-chloromethyl-2-methylquinoline, Cs2CO3, DMF (61%);
(e) urea, Mg, MeOH, at reflux (4%); (f) TBAF, THF (99%); (g)
4-chloromethyl-2-methylquinoline, Cs2CO3, DMF (87%); (h) urea,
Mg, MeOH, at reflux (19%); (i) Pd(OAc)2, HClO4, benzoquinone,
CH3CN, H2O (71%).
Mg(OMe)2 completed the synthesis of 13. Compounds
31–36 were synthesized in an analogous fashion.
Several additional dimethyl (aminomethyl)malonate
derivatives were synthesized during the SAR investiga-
tion. In one example, piperidone 14 was condensed with
dimethyl malonate under the conditions of TiCl4/pyri-
dine in THF and CCl4 (Scheme 3).9 The olefin product
was subjected to hydrogenation to yield 15. Conversion
of 15 to 16 was accomplished using the NaH/N-(bro-
momethyl)phthalimide and the hydrazine sequence de-
scribed in the synthesis of 11. Both steps proceeded in
good efficiency (93% and 90% yield, respectively). Using
conditions outlined in Schemes 1 and 2, amine 16 was
converted to compounds 37–43.
and NaH gave di-substituted malonate 4 in 52% yield.
After reduction of the olefin moiety and removal of
the silyl-protecting group, the resultant phenol was
reacted with 4-chloromethyl-2-methylquinoline and
Cs2CO3 in DMF to yield the desired 2-methylquinolin-
4-ylmethyl ether 5. Treatment with urea and Mg(OMe)2,
generated in situ, in MeOH at reflux provided pyrimi-
dinetrione 6. Truncated analogues 28 and 29 were pre-
pared in a similar fashion. Intermediate 4 was also
used to synthesize analogues 7 and 8. Toward this end,
the silyl ether in 4 was replaced with a 2-methylquino-
lin-4-ylmethyl ether via desilylation and alkylation. Sub-
sequent reaction with urea and Mg(OMe)2 in MeOH
provided pyrimidinetrione 7. Conversion of 7 to 8 was
accomplished regio-specifically in 71% yield using a
modified Wacker oxidation,7 namely palladium(II) ace-
tate, perchloric acid, and benzoquinone in CH3CN and
water.
Boc
NBoc
N
MeO2C
MeO2C
MeO2C
MeO2C
c,d
a,b
NBoc
NH2
15
16
O
14
Boc
N
NBoc
MeO2C
f,g
MeO2C
MeO2C
e
N
Br
N
MeO2C
NH2
The synthesis of a functionalized 5-(aminomethyl)py-
rimidine-2,4,6-trione analogue 13 is outlined in Scheme
2. Dimethyl methylmalonate (9) was deprotonated with
NaH and reacted with allyl bromide. The allylated prod-
uct was degraded via ozonolysis and oxidized to acid 10
using sodium chlorite. Curtius rearrangement using
diphenylphosphoryl azide (DPPA) and benzyl alcohol
provided amine 11 after removal of the Cbz group.
Alternatively, diester 9 was treated with NaH and
N-(bromomethyl)phthalimide in DMF to give 12 in
90% yield. Removal of the phthaloyl-protecting group
with hydrazine in MeOH at reflux provided amine 11.
Coupling with 4-(2-methylquinolin-4-ylmethoxy)benzo-
yl chloride8 and subsequent reaction with urea and
MeO2C
CO2Me
17
19
18
NBoc
NBoc
NBoc
MeO2C
MeO2C
h
MeO2C
MeO2C
i
MeO2C
NH2
NHCbz
NHCbz
22
20
21
Scheme 3. Reagents and conditions: (a) dimethyl malonate, TiCl4,
pyridine, THF, CCl4 (45%); (b) H2, Pd/C, MeOH (98%); (c) NaH,
N-(bromomethyl)phthalimide, DMF, 0 °C (93%); (d) NH2NH2,
MeOH, at reflux (90%); (e) 1-Boc-piperazine, K2CO3, CH3CN
(85%); (f) Bn2NH, (HCHO)n, 90 °C (43%); (g) H2, Pd(OH)2/C, Et3N,
MeOH (91%); (h) LDA, ClCO2Me, THF, ꢀ78 °C (82%); (i) H2,
Pd(OH)2/C, HCl, MeOH (100%).

268
J. J.-W. Duan et al. / Bioorg. Med. Chem. Lett. 17 (2007) 266–271
Table 1. In vitro potency in pTACE
In another synthesis, bromomalonate 17 was converted
to 18 by displacement with mono-Boc-protected pipera-
zine (Scheme 3). Mannich reaction of 18 with excess
paraformaldehyde and dibenzylamine at 90 °C proceed-
ed in 43% yield. The benzyl-protecting groups were re-
moved by hydrogenolysis to give amine 19, which was
used to prepare compounds 44–51.
O
HN
A
O
N
O
N
H
O
Compound
–A–
pTACE IC50 (lM)
1
27
28
29
6
—
–O–
1.03
1.30
2.20
49.0
>100
11.0
0.80
0.026
>100
>100
12.0
2.36
Furthermore, cyclic (aminomethyl)malonate 22 was syn-
thesized from pyrrolidine 20 (Scheme 3).10 Carbometh-
oxylation of 20 using LDA and ClCO2Me proceeded
in 82% yield. The resulting diester 21 was converted to
amine 22 upon removal of the Cbz protecting group.
Compounds 55–59 were prepared from amine 22 using
the chemistry outlined in Scheme 2. Similarly, com-
pounds 52–54 were synthesized from the corresponding
b-amino acid esters.
–CH2–
–CH2CH2–
–CH2CH2CH2–
–CH2CH@CH–a
–CH2CH2C(O)–
–CH2NHC(O)–
–NHC(O)–
7
8
13
30
31
32
26b
–CH2NHC(O)CH2–
–CH2C(O)NH–
–CH(4-pyridinyl)NHC(O)–
Scheme 4 depicts the synthesis of a pyridine-substituted
analogue 26. 4-Hydroxybenzoic acid (23) was coupled
with 4-(aminomethyl)pyridine using BOP/Hunig’s base
conditions. The phenol group was reacted with 4-chlo-
romethyl-2-methylquinoline and Cs2CO3 to yield 24.
Oxidation with OxoneÒ and NaHCO3 in MeOH and
H2O resulted in a mixture of three products, the pyri-
dine-N-oxide 25 (29%), the quinoline-N-oxide (12%),
and the bis-N-oxide (18%). Using conditions reported
by Brana et al.11 25 was condensed with 5-methylpyrim-
idine-2,4,6-trione in acetic anhydride at 80 °C to yield 26
in 32% yield.
a Trans isomer.
b Tested as a racemic mixture.
ene (29) and propylene (6) resulted in more dramatic
loss of activity (ꢁ50- and >100-fold, respectively). The
activity was restored partially with a more rigid trans-
CH2CH@CH group (7, 11 lM) and completely with a
ketone linker (8, 0.8 lM). The potency increase from 6
(>100 lM) to 8 (0.8 lM) suggested that the carbonyl
group in 8 could be involved in polar interactions with
the active site of TACE. To probe this further, the
ketone was replaced with an isosteric amide. This trans-
formation was found to have a dramatic effect as the
amide analogue 13 exhibited an IC50 of 26 nM for
pTACE, a 30-fold increase compared to the ketone
counterpart 8 and greater than 423-fold increase com-
pared to the propenylene analogue 7. The amide linker
in 13 appears to be optimal. Shortening or lengthening
the linker (30 and 31, respectively) proved detrimental
to pTACE activity. Reversal of the amide moiety also
attenuated the affinity for pTACE (32). Finally, a pyri-
dine substitution at the methylene a- to the nitrogen
resulted in a weaker inhibitor (26).
The inhibitory activity was evaluated using porcine
TACE (pTACE), as a result of its availability and
homology to human TACE.12 Compared to lead com-
pound 1, elongation with an oxygen between the pyrim-
idinetrione and the phenyl group did not significantly
alter the activity in the pTACE assay (27, Table 1).
The CH2 analogue 28 had an IC50 of 2.2 lM, 2-fold less
potent than compound 1. Further elongation with ethyl-
O
HO2C
N
H
a,b
N
Previous work from our laboratories showed that the 4-
(2-methylquinolin-4-ylmethoxy)phenyl P10 group gener-
ally gave high selectivity for TACE relative to MMP-1, -2,
and -9. Selectivity over MMP-3, -7 -12, -13, and related
aggrecanase was dependent on the nature of the
template. As summarized in Table 2, compound 13
O
OH
24
N
23
O
c
N
H
N
O
O
N
25
N
Table 2. In vitro potency of 13 in pTACE, MMPs and aggrecanase
O
O
Enzymes
lM
0.026
>4.95
d
HN
N
H
pTACE (IC50
MMP-1 (Ki)
MMP-2 (Ki)
MMP-3 (Ki)
MMP-7 (Ki)
MMP-9 (Ki)
MMP-12 (Ki)
MMP-13 (Ki)
Aggrecanase
)
O
N
H
O
O
>3.33
>4.50
N
26
>6.37
>2.13
Scheme 4. Reagents and conditions: (a) 4-(aminomethyl)pyridine,
BOP, i-Pr2NEt, DMF (54%); (b) 4-chloromethyl-2-methylquinoline,
Cs2CO3, DMSO (88%); (c) Oxone, NaHCO3, MeOH, H2O, 50 °C
(29%); (d) 5-methylpyrimidine-2,4,6-trione, Ac2O, 80 °C (32%).
>6.02
>5.02
0% at 1 lM

J. J.-W. Duan et al. / Bioorg. Med. Chem. Lett. 17 (2007) 266–271
269
displayed excellent selectivity for pTACE, but did not
show significant activity in all eight counter-screen as-
says.12 In subsequent studies, MMP-3, -7 -12, -13, and
aggrecanase were used as primary counter-screen assays.
sented differently functionalized piperidin-4-yl ana-
logues (Table 3). Potency in the pTACE assay was
largely unaffected; most compounds displayed compara-
ble potency to the methyl analogue 13, with 1-Piv-pip-
eridin-4-yl analogue 42 being most potent at 13 nM.
These compounds also maintained good selectivity over
the four MMPs and aggrecanase. For piperazine ana-
logues (44–51), most compounds showed comparable
or better potency for pTACE than 13. Most notably,
the IC50 values for the isopropyl, acetyl, and metha-
nesulfonyl piperazine analogues (47, 48, and 51, respec-
tively) were all less than 10 nM. The potency of 51
(2 nM) compared favorably to those of many hydroxa-
mate-based inhibitors reported in the literature.1b Com-
pound 51 was also greater than 500-fold selective in all
five counter-screen assays. Unfortunately, the majority
of the compounds in Table 3 suffered from poor activity
in the WBA. The most active compounds (42, 43, and
50) showed IC50 values between 35 and 40 lM.
In spite of the high affinity for pTACE, compound 13
did not inhibit TNFa production in a LPS-stimulated
human whole blood assay (WBA, IC50 > 50 lM). Be-
cause most TACE activity is intracellular,13 activity in
this assay relies on the ability of the inhibitor to pene-
trate into the cells. In addition, the whole blood assay
is complicated by the effects of protein binding. In an at-
tempt to gain additional binding potency for the
pTACE and impart functional activity in WBA, a series
of analogues was evaluated by replacing the methyl
group at the 5-position of the pyrimidine-2,4,6-trione
(R group, Table 3). Aliphatic groups, such as ethyl
(33), benzyl (34), and isopropyl (35), all gave pTACE
inhibitors of essentially the same potency as 13. The
Boc-protected amino analogue (36) was also compara-
ble. In all cases, good selectivity over MMP-3, -7, and
aggrecanase was maintained. Selectivity over MMP-12
and, to some extent, MMP-2, appeared to depend on
the steric size of these substituents. Specifically, linear
groups such as ethyl (33) and benzyl (34) gave sub-mi-
cromolar Ki’s for MMP-12 and -2. The more bulky iso-
propyl and BocNH analogues (35 and 36) were less
active for MMP-2 and inactive in the MMP-12 assay
(>6.02 lM), hence were more selective for pTACE.
Finally, we attempted to chemically constrain the lead
molecule 13 using spiro-pyrimidinetriones (Table 4).
The cyclohexane-derived [6,6]-spiro compound 52
showed an IC50 of 0.138 lM in the pTACE assay, indi-
cating that the spiro-template was tolerated, albeit the
activity was 5-fold less than 13. The cyclopentane-de-
rived [5,6]-spiro analogue 53 displayed pTACE potency
equivalent to 13, further validating this approach.
Unfortunately, 53 was inactive in the WBA (>50 lM).
Hoping to improve the WBA activity, we decided to
introduce a tetrahydrofuran and several pyrrolidines in
place of the cyclopentane. The tetrahydrofuran-derived
spiro analogue 54 was a 44 nM inhibitor of pTACE,
Previous studies indicated that piperidine and piperazine
substituents at 5-position of the pyrimidinetrione could
improve affinity for TACE.3 Compounds 37–43 repre-
Table 3. In vitro potency in pTACE, MMP-2, -3, -7, -12, aggrecanase, and WBA
O
HN
R
O
HN
NH
O
N
O
O
Compound
R
pTACE
IC50 (lM) (lM)
MMP-2 Ki MMP-3 Ki MMP-7 Ki MMP-12 Ki Aggrecanase
(lM)
WBA IC50
(lM)
(lM)
(%) inh at 1 lM (lM)
33
34
35
36
37
38
39
40
Et
Bn
0.016
0.018
0.019
0.013
0.055
0.057
0.052
0.031
0.20
0.37
>4.50
3.69
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
0.21
0.39
18
34
11
16
1
>50
>50
>50
>50
i-Pr
BocNH
0.93
>4.50
>4.50
>4.50
>4.50
>4.50
>4.50
>6.02
>6.02
>6.02
>6.02
>6.02
>6.02
>3.33
>3.33
>3.33
>3.33
>3.33
piperidin-4-yl
1-Me-piperidin-4-yl
1-i-Pr-piperidin-4-yl
1-(tetrahydropyran-4-yl)-
piperidin-4-yl
1-Ms-piperidin-4-yl
1-Piv-piperidin-4-yl
1-Boc-piperidin-4-yl
4-Me-piperazin-1-yl
48.7
15
21
5
>50
>50
>50
41
42
43
44
45
46
47
48
49
50
51
0.029
0.013
0.047
0.058
>3.33
>3.33
>3.33
>3.33
>3.33
2.7
>4.50
>4.50
>4.50
>4.50
>4.50
>4.50
>4.50
>4.50
>4.50
>4.50
>4.50
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
>6.02
>6.02
>6.02
>6.02
>6.02
4.1
36
10
0
>50
39
35
21
26
22
20
21
36
7
>50
>50
>50
>50
>50
43
4-(propargyl)piperazin-1-yl 0.062
4-Bn-piperazin-1-yl
4-i-Pr-piperazin-1-yl
4-Ac-piperazin-1-yl
0.014
0.007
0.005
>3.33
>3.33
>3.33
0.02
>6.02
>6.02
4.64
4-(nicotinoyl)piperazin-1-yl 0.010
4-Piv-piperazin-1-yl
4-Ms-piperazin-1-yl
0.029
0.002
0.05
1.02
38
>50
2.17
11

270
J. J.-W. Duan et al. / Bioorg. Med. Chem. Lett. 17 (2007) 266–271
Table 4. In vitro potency in pTACE, MMP-2, -3, -7, -12, aggrecanase, and WBAa
X
O
O
HN
N
H
O
N
H
O
O
N
Compound
–X–
pTACE
IC50 (lM)
MMP-2
Ki (lM)
MMP-3
Ki (lM)
MMP-7
Ki (lM)
MMP-12
Ki (lM)
MMP-13
Ki (lM)
Aggrecanase
(%) inh at 1 lM
WBA IC50
(lM)
b
b
b
b
b
52
53
54
55
56
57
58
59
–(CH2)2–
–CH2–
–O–
0.138
0.024
0.044
0.055
0.111
0.029
0.036
0.128
0.11
>3.33
>3.33
>3.33
>3.33
>3.33
>3.33
>3.33
—
—
—
—
29
0
—
b
—
b
—
b
—
b
—
>50
50
>4.50
>4.50
>4.50
>4.50
>4.50
>4.50
>6.37
>6.37
>6.37
>6.37
>6.37
>6.37
4.04
0.58
3.53
3.95
12
44
53
17
26
44
–N(Ac)–
–N(Piv)–
–N(nicotinoyl)–
–N(Ms)–
–N(Boc)–
14
b
—
>6.02
0.13
1.29
>50
18.4
12.6
14
1.31
3.72
1.03
>5.21
a All compounds were tested as racemic mixture.
b Not tested.
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ase, but failed to improve potency in the WBA notice-
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spiro analogues exhibited promising activity in the
WBA. Compounds 55, 57, 58, and 59 all had IC50 values
under 20 lM. These compounds also maintained good
overall selectivity.
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Robinson, R. P.; Subramanyam, C.; Vaughn-Bowser, M.
L.; Yocum, S. A. Bioorg. Med. Chem. Lett. 2005, 15, 1807;
(g) Kim, S.-H.; Pudzianowski, A. T.; Leavitt, K. J.;
Barbosa, J.; McDonnell, P. A.; Metzler, W. J.; Rankin, B.
M.; Liu, R.; Vaccaro, V.; Pitts, W. Bioorg. Med. Chem.
Lett. 2005, 15, 2970.
In summary, a new series of TACE inhibitors was dis-
covered using a pyrimidine-2,4,6-trione as a hydroxa-
mate replacement. Even though pyrimidinetrione is a
significantly weaker ligand for zinc ion than hydroxamic
acid, highly potent TACE inhibitors have been identified
through optimization of the rest of the molecule. The
most potent compound 51 had an IC50 of 2 nM in the
pTACE-binding assay. To the best of our knowledge,
51 represents the first example of non-hydroxamate
TACE inhibitors with single digit nanomolar potency.
Some of the analogues also displayed moderate func-
tional activity in a cellular assay. However, further
improvement in functional activity is needed for these
inhibitors to be useful in vivo.
Acknowledgments
5. (a) 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;
(b) Wasserman, Z. R.; Duan, J. J.-W.; Voss, M. E.; Xue,
C.-B.; Cherney, R. J.; Nelson, D. J.; Hardman, K. D.;
Decicco, C. P. Chem. Biol. 2003, 10, 215.
The authors thank John Giannaras, Sherrill Nurnberg,
and Paul Strzemienski for assistance in enzymatic and
cell assays.
6. Young, S. D.; Payne, L. S.; Thompson, W. J.; Gaffin, N.;
Lyle, T. A.; Britcher, S. F.; Graham, S. L.; Schultz, T. H.;
Deana, A. A.; Darke, P. L.; Zugay, J.; Schleif, W. A.;
Quintero, J. C.; Emini, E. A.; Anderson, P. S.; Huff, J. R.
J. Med. Chem. 1992, 35, 1702.
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