Synthesis and structure-activity relationship of a novel, achiral series of TNF-α converting enzyme inhibitors

Article abstract of DOI:10.1016/j.bmcl.2006.02.015

A novel series of achiral TNF-α converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11 nM in a porcine TACE assay and inhibited TNF-α production in an LPS-stimulated whole blood assay with an IC₅

Full text of DOI:10.1016/j.bmcl.2006.02.015

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2699–2704
Synthesis and structure–activity relationship of a novel,
achiral series of TNF-a converting enzyme inhibitors
John L. Gilmore,* Bryan W. King, Cathy Harris, Thomas Maduskuie, Stephen E. Mercer,
Rui-Qin Liu, Maryanne B. Covington, Mingxin Qian, Maria D. Ribadeneria,
Krishna Vaddi, James M. Trzaskos, Robert C. Newton,
Carl P. Decicco and James J.-W. Duan
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
Received 12 January 2006; revised 6 February 2006; accepted 7 February 2006
Available online 3 March 2006
Abstract—A novel series of achiral TNF-a converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited
activities from 0.35 to 11 nM in a porcine TACE assay and inhibited TNF-a production in an LPS-stimulated whole blood assay
with an IC50 value of 23 nM for the most potent one. They also have excellent selectivities over related metalloproteases including
aggrecanases.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Tumor necrosis factor-a (TNF-a)1 is a potent proin-
flammatory cytokine which is primarily produced by
monocytes and macrophages and exists as a 26 kD
membrane bound propeptide (pro-TNF-a). Pro-TNF-a
is processed by sheddases to release the 17 kD soluble
form (s-TNF-a). Disregulation of TNF-a is implicated
in chronic inflammatory diseases such as rheumatoid
arthritis, psoriasis, and Crohn’s disease.2 Marketed biol-
ogics that work by sequestering pro-TNF-a and s-TNF-
a, such as enbrel, remicade, and humira, have clinically
validated anti-TNF therapy for the treatment of these
chronic inflammatory diseases.3 While these biologics
are effective, they are expensive and must be adminis-
tered parenterally.
desirable since some broad spectrum and partially selec-
tive MMP inhibitors have been reported to cause mus-
culoskeletal side effects.6 This paper will disclose a
novel series of selective, achiral TACE inhibitors.
Earlier efforts in our TACE program led to the discov-
ery of an acyclic b-aminohydroxamic acid analog 1
(Fig. 1). This compound has an IC50 of 1 nM in a
pTACE7 assay and is selective against several matrix
metalloproteinases (MMPs); however, it is not effective
H
N
O
OR
O
O
α,β
HO
H
N
HO
cyclization
N
N
H
H
An alternate approach is to inhibit the release of s-TNF-
a via inhibitors of TNF-a converting enzyme (TACE).
TACE is a member of the metzincin family and is the
primary sheddase for releasing soluble TNF-a from
cells.4 It has been shown that inhibition of TACE blocks
soluble TNF-a release; thus, a small molecule that can
selectively inhibit TACE may represent a valid approach
to anti-TNF-a therapy.5 Selectivity over other MMPs is
X
O
OR
1
β,β
2
cyclization
α,α
cyclization
OR
O
O
H
H
HO
N
N
N
N
HO
H
H
O
O
OR
R =
X
X
3
4
Keywords: TACE inhibitors; Metazincin; Metalloprotease; Sheddase;
Tumor necrosis factor; Antiinflammatory; Hydroxamic acid.
N
*
Corresponding author. Tel.: +1 609 252 3153; e-mail:
john.gilmore@bms.com
Figure 1. b-Aminohydroxamic acid series (1–4).
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.015

2700
J. L. Gilmore et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2699–2704
in inhibiting TNF-a production in human whole blood
assay (WBA). In classic fashion, this compound is
thought to work by forming a bidentate bond between
the hydroxamic acid moiety and the catalytic Zn ion
in the active site. Additionally, the carbonyl group of
the central amide forms two important hydrogen bonds
to Gly163 and Leu164 of the protein backbone.8 The
[(2-methyl-4-quinolinyl)methoxy]phenyl P10 group is
the critical determinant of selectivity for TACE relative
to other MMPs.9–11
nitrogen. The final step was conversion of the methyl es-
ter to the hydroxamic acid using a hydroxylamine/
KOH/MeOH solution to give compounds 7a,b, and d–
g. The Boc-protected compound 7b was deprotected
with TFA to give 7c.
These compounds were tested and found to have activ-
ities ranging from 2 to 12 nM in the pTACE assay and
were selective against other MMPs (data not shown);
however, they showed no WBA activity (Table 1).
In an effort to discover compounds which have both
pTACE as well as WBA activities, several series of cyc-
lic-b-aminohydroxamic acids were designed and synthe-
sized (2–4). The first series was formed by cyclizing a,b
to the hydroxamic acid (Fig. 1, 2). The synthesis and
evaluation of these compounds will be disclosed in
another paper.12 Alternatively, we envisioned generation
of two new series formed by cyclizing a,a and b,b to the
hydroxamic acid (Fig. 1, 3 and 4).
The scaffold was then modified by migrating the ring
attachment from the a-carbon to the b-carbon (Fig. 1,
4). Although there is no substitution a to the hydroxa-
mic acid to help prevent possible metabolism, this skel-
eton is ‘neopentyl like’ with regard to the hydroxamic
acid and it was hoped that this would provide enough
steric hindrance to prevent metabolism of the hydroxa-
mic acid.
These compounds were synthesized according to
Scheme 2. Ketone 8 was subjected to a Wittig olefin-
ation to provide esters 9a,b, and z. Addition of ammonia
in a Michael fashion proceeded in good yield at 80 ꢁC in
a sealed tube to provide amines 10a,b, and z. These
amines were coupled to the P10 side chain using BOP re-
agent to give esters 11a,b, and z. The Boc-protected
piperidine compound 11b was deprotected with TFA
to give 11c and then functionalized with a variety of R
groups to afford compounds 11d–y. Finally, the methyl
ester was converted to a hydroxamic acid by treatment
of a hydroxylamine/KOH/MeOH solution to afford
compounds 12a–z.
The a,a cyclization series was studied first. The a,a sub-
stitution was designed to help in vivo stability of the
hydroxamic moiety through steric hindrance since this
is known to be a problem in other series. The synthesis
of the a,a-cyclic-b-aminohydroxamic acids (7a–g) is out-
lined in Scheme 1. Methyl cyanoacetate was alkylated
with various dibromides followed by reduction of the ni-
trile using platinum oxide to afford the cyclic primary
amines 5a,b, and g. These amines were coupled to the
P10 side chain 4-[(2-methyl-4-quinolinyl)methoxy]benzo-
ic acid using BOP reagent to afford compounds 6a,b,
and g. Compound 6b was deprotected using TFA to give
6c; which was further functionalized at the piperidine
These b,b-cyclic b-aminohydroxamic acid analogs were
tested for their activities (Table 2). All the compounds
in this series were active in the pTACE assay with
IC50s ranging from 1 to 8 nM. The excellent selectivities
for these compounds against MMP-1, -2, -9, and -13 can
be attributed to the [(2-methyl-4-quinolinyl)methoxy]-
phenyl P10 group.8 The cyclohexyl derivative, 12a,
exhibited some WBA activity at 737 nM. Replacing
the cyclohexyl with a piperidine scaffold gave more
exciting results. The first compound prepared in this ser-
ies was the Boc-protected piperidine 12b. This com-
pound was twice as potent in the WBA as 12a at
370 nM. Removal of the Boc group to give 12c resulted
in a compound which was remarkably potent in the
O
O
NH2
O
a,b
X
CN +
Br
Br
O
c
X
(X = CH2, NBoc, O)
5a: X = CH2
5b: X = NBoc
5g: X = O
O
O
O
N
H
e or f, g
O
X
N
6a: X = CH2
6b: X = NBoc
6c: X = NH
d
6g: X = O
Table 1. In vitro potency of 7a–g in pTACE and WBA
O
O
Compound
X
pTACE Inhibition
a
IC50 (nM)
WBA
b
HO
IC50 (lM)
N
N
H
H
7a
7b
7c
7d
7e
7f
CH2
NBoc
NH
8.6
2.4
4.9
11
>3.0
>3.0
>3.0
>3.0
>3.0
>3.0
>3.0
O
X
N
7a-g
N-Propyl
N(CO)tBu
N-SO2Me
O
2.3
1.9
2.3
Scheme 1. Reagents and conditions: (a) NaH or K2CO3, THF; (b)
PtO2, H2, MeOH, concd HCl; (c) 4-[(2-methyl-4-quinolinyl)meth-
oxy]benzoic acid, BOP reagent, N-methylmorpholine, DMF; (d) TFA,
CH2Cl2; (e) various acids, BOP reagent, N-methylmorpholine, DMF;
(f) propionaldehyde NaH(OAc)3, 1,2-dichloroethane; (g) NH2OH,
KOH, MeOH.
7g
a pTACE IC50 and MMP Ki values are from a single determination.
b Inhibition of TNF-a release in WBA was determined with three
donors.

J. L. Gilmore et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2699–2704
2701
Compound 12h which had a pKa of 7.75 and a Caco-2
Papp of 2.4 · 10ꢀ6 cm/s and compound 12p which had
a pKa of 6.06 and a Caco-2 Papp of 0.55 · 10ꢀ6 cm/s.
While there appears to be a good correlation of LogP
with Caco-2, many compounds were found in this series
with high LogP values (>3.5) and low Caco-2 perme-
ability (data not shown).
CO2Me
O
O
NH2
c
b
a
O
X
X
X
10a: X = CH2
10b: X = NBoc
10z: X = O
CH
9a: X = CH2
9b: X = NBoc
9z: X = O
8a: X =
8b: X = NBoc
8z: X = O
2
The next series examined were non-basic derivatives
(12r–z). These derivatives included amides, sulfona-
mides, and ureas of piperidines and a tetrahydropyran.
Once again, these compounds had excellent pTACE
activities ranging from 0.35 to 3 nM. The WBA activi-
ties were also good ranging from 23 to 212 nM. Com-
pound 12r, which has an acetyl group on the
piperidine, was exceptionally good in the WBA at
23 nM. The Caco-2 permeability was not improved sig-
nificantly in this series, and even extremely lipophilic
compounds such as 12u and v gave marginal Caco-2
permeability.
N
O
H
O
N
e or f, g
O
X
O
11a: X = CH2
11b: X = NBoc
11c: X = NH
11z: X = O
d
N
O
H
N
H
N
Many of these compounds were also evaluated in an
LPS-mouse model and were found to have good anti-
TNF-a activity. Compounds 12c,l,r,y and z all had
ED50s of less than 8 mg/kg after oral administration
(Table 2). Despite the low to marginal Caco-2 values,
12c and z were examined in more depth. In an expanded
panel of counterscreens, both compounds have excellent
selectivity (>1000·) for pTACE relative to MMP-1, -2, -
9, -13, -14, -15, and -16. Compound 12c also showed
over 50-fold selectivity for pTACE over MMP-3,
MMP-8, ADAMTS-1, and ADAMTS-5, and 10-fold
selectivity over MMP-7. Compound 12z was found to
be the more selective of the two with >1000-fold selectiv-
ity over MMP-8, ADAMTS-1, ADAMTS-4, and
ADAMTS-5 as well as more than 80-fold selectivity
over MMP-3 and MMP-7 (Table 4).
HO
O
O
X
12a-z
Scheme 2. Reagents and conditions: (a) Ph3P@CHCO2Me, PhMe, D;
(b) NH3, MeOH, 80 ꢁC, sealed tube; (c) 4-[(2-methyl-4-quinoli-
nyl)methoxy]benzoic acid, BOP reagent, N-methylmorpholine, DMF;
(d) TFA, CH2Cl2; (e) various acids, BOP reagent, N-methylmorpho-
line, DMF; (f) various aldehydes NaBH(OAc)3, 1,2-dichloroethane; (g)
NH2OH, KOH, MeOH.
WBA assay with an IC50 of 36 nM; however, 12c was
found to have very low Caco-2 permeability. An effort
was made to try to increase the Caco-2 permeability
by substituting the piperidine nitrogen.
The first series prepared were alkyl substituents on the
piperidine nitrogen (12d–m). When increasingly lipo-
philic groups were introduced on the piperidine, there
was an increase in Caco-2 permeability in compounds
12h,i, and l; however, these compounds were less active
in the WBA by 4- to 10-fold.
Studies using S9 liver cells were performed to assess the
metabolic stability of 12c and z. The stability of 12c was
excellent despite not having a substituent next to the
hydroxamic acid. After incubation in S9 liver cells for
30 min at 37 ꢁC, 100% of the parent compound was
remaining in rat, dog, and chimp and 92% of the parent
compound was remaining in human. Compound 12z
was less stable. After 30 min incubation in S9 liver cells,
83.8% remained in human and 36.7% in chimps.
It was postulated that the high basicity of the piperidine
nitrogen was preventing Caco-2 permeation. To try to
improve the physical properties, additional piperidine
derivatives 12n–q were prepared which contained groups
that would reduce the basicity of the piperidine nitrogen.
Again these derivatives exhibited excellent pTACE
activities. Compounds 12o,p, and q exhibited marginal
Caco-2 permeabilities and had WBA activities ranging
from 45 to 119 nM.
Next, the pharmacokinetic profiles of these two com-
pounds was evaluated (Table 5). The pharmacokinetics
of 12c was studied in Beagle dogs and Sprague–Dawley
rats in a cassette dose fashion (n = 3) and the pharmaco-
kinetics of 12z was studied in the same two species in a
discrete fashion. The compounds were administered
intravenously and orally, and the plasma levels were
analyzed by LC–MS–MS assay. Compound 12c exhibit-
ed very low clearance in both species. This compound
also showed low oral bioavailability as indicated by
the F% values of 8 and 17. In dogs, compound 12z
had high systemic clearance with a terminal half-life of
4.2 h after iv administration. The volume of distribution
at steady state was moderate at 2.5 L/kg. Oral bioavail-
ability was excellent with an F% of 79. In rats, the clear-
Several compounds were selected to evaluate the rela-
tionship between the pKa of the piperidine nitrogen,
lipophilicity (HPLC LogP), and the Caco-2 permeation.
As shown in Table 3, there seems to be an inverse corre-
lation between the basicity of the piperidine nitrogen
and Caco-2 permeation. The Caco-2 values were low un-
til the pKa of the piperidine was below 7. Of the com-
pounds studied, only two were outlying compounds.

2702
J. L. Gilmore et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2699–2704
Table 2. In vitro and in vivo profile of 12a–z
Compound
X
pTACE
Inhibition IC50 (nM) Ki (nM) Ki (nM) Ki (nM) Ki (nM) Papp
WBA
b
MMP-1 MMP-2 MMP-9 MMP-13 Caco-2
LPS-mousec at
10 mg/kg (po)
(·10ꢀ6 cm/s)
a
IC50 (nM)
12a
12b
12c
12d
12e
12f
12g
12h
12i
CH2
NBoc
NH
1.4
7.7
1.9
3.1
2.2
2.0
3.7
2.6
2.3
1.9
737
370
36
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>5025
>5025
>5025
>5025
>5025
>5025
>5025
>5025
>5025
>5025
3.6
8.2
0.0
0.1
0.1
0.1
0.1
2.4
3.2
0.5
Not determined
Not determined
ED50 < 3.0 mg/kg
17%
N-Methyl
N-Ethyl
N-Propyl
N-tBu
109
26
Not determined
Not determined
29%
96
56
t
N-CH2 Bu
N-Di-me-propargyl
N-Phenyl
143
490
52%
at 3 lM
290
272
50
38%
Not determined
Not determined
12j
12k
12l
N-Benzyl
N-(CH3)2COOtBu
N-(CH3)2COOH
1.8
1.9
3.2
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>4949
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>3333
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>2128
>5025
2462
0.1
5.3
Not determined
ED50 = 7.8 mg/kg
24%
100%d
12m
12n
12o
12p
12q
12r
12s
12t
>5025
>5025
>5025
>5025
3136
0.1
0.1
N-2-(4,5-Dihydrothiazole) 1.2
30
45
N-CH2CH2SO2Me
N-CH2CH2SO2Et
N-CH2CH2F
N-C(O)Me
1.2
1.4
2.6
1.9
2.7
1.2
2.1
1.9
2.2
1.0
0.81
0.55
0.55
0.1
Not determined
Not determined
Not determined
ED50 = 1.4 mg/kg
5%
119
90
23
39
>5025
>5025
>5025
>5025
>5025
>5025
>5025
N-C(O)Et
N-C(O)iPr
0.1
0.2
89
17%
12u
12v
12w
12x
N-C(O)tBu
N-C(O)CH2 Bu
102
212
105
54
0.88
0.79
0.56
Not
determined
Not
determined
0.8
ED50 = 25.5 mg/kg
Not determined
48%
t
N-C(O)iBu
N-SO2Me
Not determined
12y
N-C(O)NMe2
2.8
152
>4949
>4949
>3333
>3333
>2128
>2128
>5025
>5025
ED5 < .3.0 mg/kg
ED50 = 4.7 mg/kg
12z
O
0.35e
150
a pTACE IC50 and MMP Ki values are from a single determination.
b Inhibition of TNF-a release in WBA was determined with three donors.
c See Ref. 11 for LPS-mouse model studies.
d LPS-mouse for 12n is from ip administration.
e This is a Ki value.
Table 3. pKa, LogP, and Caco-2 relationship
Table 4. Selectivity profile of 12c and z
Compound pKa
HPLC LogP Caco-2 Papp (·10ꢀ6 cm/s)
Enzyme
12c Ki (nM) 12z Ki (nM)
12a
12g
12c
12h
12q
12n
12i
10.1
ꢁ9
1.62
1.95
2.13
0
pTACE
1.9a
>4949
0.35
>4949
0.1
0.1
2.4
0.2
0.1
3.2
5.3
0.55
MMP-1 (collagenase)
MMP-2 (gelatinase A)
MMP-3 (stremolysin-1)
MMP-7 (matrilysin)
MMP-8 (collagenase-2)
MMP-9 (gelatinase B)
MMP-13 (collagenase-3)
8.4
>3333
91
18
>3333
82
25
7.75 3.66
7.2 2.70
7.23 2.78
6.58 3.43
217
>2128
>5025
>3100
>2128
>5025
>5290
>7088
>5554
7800
12l
12p
6.4 4.38
6.06 2.48
MMP-14 (membrane type-1 MMP) >5290
MMP-15 (membrane type-2 MMP) >7088
MMP-16 (membrane type-3 MMP) >5554
ADAMTS-1
ADAMTS-4 (aggrecanase-1)
ADAMTS-5 (aggrecanase-2)
776
1834
97
ance (1.6 L/h/kg) was comparable to the dog study and
the half-life (0.3 and 1.8 h) and volume of distribution at
steady state (0.3 L/kg) were lower. Additionally, the oral
bioavailability was not as good (15%).
4600
1900
a This is an IC50 value.
In summary, we have discovered a novel, achiral series
of TACE inhibitors. Our most promising compounds
come from a series of b,b-cyclic b-aminohydroxamic
acid analogs. As a class, these compounds have excel-
lent pTACE activities, good WBA activities, and were
very selective over other MMPs. Within this series,
compound 12z, which has a cyclic tetrahydropyran
substitution at the b,b position, is our most promising
lead. This compound exhibited a Ki of 0.35 nM in
pTACE assays and an IC50 of 150 nM in WBA. De-
spite having low to moderate Caco-2 permeability,
12z had good oral anti-TNF-a activity in the LPS
model. Pharmacokinetic studies demonstrated that it

J. L. Gilmore et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2699–2704
Table 5. Pharmacokinetic profiles of 12c and z in dogs and rats
2703
Compound
Dose (mg/kg)
Cl (L/h/kg)
0.3
t1/2
Vss (L/kg)
Tmax (h)
0.63
0.3
Cmax (nM)
AUC (nM h)
F (%)
12c (Dog: N-in-1)a
iv 0.5
po 1.0
1.5
2.1
0.3
2185
343
126
8
17
79
15
12c (Rat: N-in-1)a
12z (Dog: discrete)b
12z (Rat: discrete)b
iv 3.3
po 6.7
0.6
2.3
1.6
2.1
2.2
0.3
2.5
0.7
11359
8358
2484
iv 2.0
po 10.0
4.2
4.0
1966
7720
0.75
0.4
4488
iv 2.0
po 30
0.3
1.8
2208
4860
3745
a N-in-1 studies used an n = 3.
b Discrete dog and rat study is an average of three animals.
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.
was orally bioavailable with an F value of 79% in dog
and 15% in rat.
5. (a) Newton, R. C.; Decicco, C. P. J. Med. Chem. 1999, 42,
2295; (b) Nelson, F.; Zask, A. Expert Opin. Invest. Drugs
1999, 8, 383.
Acknowledgment
We thank John Giannaris, Sherrill Nurnberg, and Paul
Streminski for carrying out the enzyme and cell assays.
We also thank Dr. Jim Sheppeck for a critical review
of the manuscript.
6. (a) Nemunaitis, J.; Poole, C.; Primrose, J.; Rosemurgy, A.;
Malfetano, J.; Brown, P.; Berrington, A.; Cornish, A.;
Rasmussen, H.; Kerr, D.; Cox, D.; Millar, A. Clin. Cancer
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260, 2345.
2. (a) Aggarwal, B. B.; Natarajan, K. Eur. Cytokine Network
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7. pTACE = porcine TACE.
8. Duan, J. J.-W.; Lu, Z.; Xue, C.-B.; He, X.; Seng, J.;
Roderick, J.; Wasserman, Z. R.; Liu, R.-Q.; Covington,
M. B.; Magolda, R. L.; Newton, R. C.; Trzaskos, J.;
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9. For a recent review of TACE inhibitors, see: Skotnicki, J.
S.; Levin, J. I. Annu. Rep. Med. Chem. 2003, 38, 153.
10. For selective TACE inhibitors reported from our group:
(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) Xue,
C.-B.; Voss, M. E.; Nelson, D. J.; Duan, J. J.-W.; Cherney,
R. J.; Jacobson, I. C.; He, X.; Roderick, J.; Chen, L.;
Corbett, R. L.; Wang, L.; Meyer, D. T.; Kennedy, K.;
DeGrado, W. F.; Hardman, K. D.; Teleha, C. A.; Jaffee,
B. D.; Liu, R.-Q.; Copeland, R. A.; Covington, M. B.;
Christ, D. D.; Trzaskos, J. M.; Newton, R. C.; Magolda,
R. L.; Wexler, R. R.; Decicco, C. P. J. Med. Chem. 2001,
44, 2636; (c) Xue, C.-B.; He, X.; Corbett, R. L.; Roderick,
J.; Wasserman, Z. R.; Lu, 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; (d) 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;
(e) Cherney, R. J.; Duan, J. J.-W.; Voss, M. E.; Chen, L.;
Meyer, D. T.; Wasserman, Z. R.; Hardman, K. D.; Liu,
R.-Q.; Covington, 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; (f) Xue, C.-B.; He, X.; Roderick, J.; Corbett, R. L.;
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K. L.; Reddy, P.; Srinivasan, S.; Nelson, N.; Bolani, N.;
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Johnson, R. S.; Paxton, R. J.; March, C. J.; Cerretti, D. P.
Nature 1997, 385, 729; (b) Moss, M. L.; Jin, S. J. D.-L. C.;
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-

2704
J. L. Gilmore et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2699–2704
Duan, J. J.-W.; Liu, R.-Q.; Covington, M. B.; Newton, 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.;
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Cheung, K.; Cole, D.; Crago, C.; Santos, E. D.; Du, X.;
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Zask, A.; Cummons, T.; Sung, A.; Xu, J.; Zhhang, Y.;
Xu, W.; Ayral-Kaloustian, S.; Jin, G.; Cowling, R.;
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T.; Shimano, M. Bioorg. Med. Chem. Lett. 2004, 43,
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11. For selective TACE inhibitors from other groups: (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; (b) 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; (c) Chen, J. M.; Jin, G.; Sung, A.; Levin, J. I.
Bioorg. Med. Chem. Lett. 2002, 12, 1195; (d) 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.;
March, C. J.; Mohler, K. M.; Black, R. A.; Skotnicki, J.
S. Bioorg. Med. Chem. Lett. 2002, 12, 1199; (e) Letavic,
M. A.; Axt, M. Z.; Barberia, J. T.; Carty, T. J.; Danley,
D. E.; Geoghegan, K. F.; Halim, N. S.; Hoth, L. R.;
12. Duan J. J.-W.; Chen, L; Lu, Z.; Xue, C.-B.; Liu, R.-Q.;
Covington, M. B.; Qian, M.; Wasserman, Z. R.; Vaddi,
K.; Christ D. D.; Newton, R. C.; Decicco C. P. Submitted
for publication.