Design and synthesis of 3,3-piperidine hydroxamate analogs as selective TACE inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.05.022

Structure-based methods were used to design β-sulfone 3,3-piperidine hydroxamates as TACE inhibitors with the aim of improving selectivity for TACE versus MMP-13. Several compounds in this series were synthesized and evaluated in enzymatic and cell-based

Full text of DOI:10.1016/j.bmcl.2007.05.022

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4333–4337
Design and synthesis of 3,3-piperidine hydroxamate analogs
as selective TACE inhibitors
Henry-Georges Lombart,a,* Eric Feyfant,a Diane Joseph-McCarthy,a Adrian Huang,a
Frank Lovering,a LinHong Sun,c Yi Zhu,c Congmei Zeng,c
Yuhua Zhangc, and Jeremy Levinb
aChemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA
bChemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA
cInflammation, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA
Received 13 February 2007; revised 7 May 2007; accepted 9 May 2007
Available online 16 May 2007
Abstract—Structure-based methods were used to design b-sulfone 3,3-piperidine hydroxamates as TACE inhibitors with the aim of
improving selectivity for TACE versus MMP-13. Several compounds in this series were synthesized and evaluated in enzymatic and
cell-based assays. These analogs exhibit excellent in vitro potency against isolated TACE enzyme and show good selectivity for
TACE over the related metalloproteases MMP-2, -13, and -14.
Ó 2007 Elsevier Ltd. All rights reserved.
TACE (TNF-a converting enzyme, ADAM-17) is the
zinc protease responsible for the release of soluble
TNF-a (tumor necrosis factor-a) from parent mem-
brane-bound pro-TNF-a.1 TNF-a, a cytokine, is an
important mediator of immuno-inflammatory responses
of other pro-inflammatory cytokines. These cytokines
have been linked to the pathogenesis of rheumatoid
arthritis (RA)2 and are involved in promoting inflamma-
tion as well as bone and cartilage destruction. The clin-
ical success of TNF-a soluble receptor etanercept
(EnbrelÒ)3 and TNF-a monoclonal antibodies inflix-
imab (RemicadeÒ)4 and adalimumab (HumiraÒ)5 has
validated TNF as a target for the treatment of inflam-
matory diseases such as RA and psoriasis. While these
biologics are effective, they are costly and must be
administered via parenteral injection. The development
of orally active small molecule TACE inhibitors is there-
fore a highly desirable goal for the treatment of RA and
related diseases.
trum inhibitors of TACE and related matrix
metalloproteases (MMPs), have been reported in the lit-
erature.6 Because various MMPs are overexpressed in
RA synovial tissue and contribute to joint destruction,7
it may be therapeutically advantageous to inhibit such
MMPs in addition to TACE. However, since side effects
from broad spectrum MMP inhibitors have been
observed in clinical studies,8 more selective inhibitors
of TACE may demonstrate improved safety margins
on long term dosing.
Earlier efforts at Wyeth led to the discovery of TACE
inhibitors bearing a butynyloxy P10 moiety that have
shown excellent in vitro potency against TACE and
good selectivity over some MMPs (e.g., MMP-1 and
-9).9–12 Structural analysis suggests that this particular
P10 moiety, on some inhibitor scaffolds, introduces a
level of selectivity over various MMPs because of its
tight fit in the channel between the S10 and S30 pockets
of TACE, and the inability of some MMPs to accommo-
date its length and rigidity. The selectivity of these com-
pounds over MMPs that possess deep S10 pockets (e.g.,
MMP-13) generally remains low, but varies depending
on the scaffold that bears the hydroxamic acid. Two
such analogs, thiomorpholine–sulfonamides 1a and 1b
(Fig. 1), are orally bioavailable dual TACE/MMP inhib-
itors with excellent potency in human whole blood.10
Compound 1b has entered clinical trials for the treat-
In the past few years, a number of selective small mole-
cule inhibitors of TACE, as well as more broad spec-
Keywords: Inflammation; TACE; Rheumatoid arthritis.
*
Corresponding author. Tel.: +1 617 665 5636; fax: +1 617 665
5682; e-mail: hglombart@wyeth.com
Present address: Procter & Gamble Pharmaceuticals, 8700 Mason
Montgomery Road, Mason, OH 45040, USA.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.022

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H.-G. Lombart et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4333–4337
O
S
N
To apply these observations to the design of TACE
O
O
O
O
O
HO
S
O
inhibitors and exploit the differences in the TACE and
MMP S1 pockets, we sought to introduce sterically
demanding P1 groups at the piperidine nitrogen of a
3,3-piperidine scaffold in order to increase selectivity
for TACE over MMP-13 (Figs. 2 and 3).
O
HO
N
H
N
S
R
1a (R = H)
1b (R = OH)
2
Cl
The desired 3,3-piperidine b-sulfone hydroxamates were
prepared via the synthetic route shown in Scheme 1.
Ethyl piperidine-3,3-carboxylate 4 was Boc protected
and a-iodomethylation of 5 afforded ester 6. Alkylation
O
O O2S
HO
N
H
N
O
O
O
S
O
O O2S
O O2S
3
HO
HO
N
N
H
H
Figure 1. Thiomorpholine sulfonamide and piperidine sulfone TACE
inhibitors.
N
N
R
O
S
O
S1 Pocket
ment of RA.10c While these thiomorpholines show little
selectivity for TACE versus MMPs, we have found that
a series of a-sulfone piperidines, exemplified by com-
pound 2, exhibit good in vitro potency against TACE
and some selectivity for TACE over MMP-1, -9, and
-13.11 Similarly, 4,4-piperidine b-sulfone hydroxamic
3
Figure 3. Design of 3,3-piperidine hydroxamic acid TACE inhibitors
based on b-sulfone 4-piperidine analogs 3.
acid 3 (Fig. 1) has excellent TACE activity (IC50
1.5 nM) and greater than 150-fold selectivity over both
MMP-2 and -13.12
=
EtO
O
EtO
O
N
O
EtO
I
a
b
NH
N
Boc
Boc
The selectivity exhibited by some 4,4-piperidine b-sul-
fone TACE inhibitors is believed to reflect structural dif-
ferences between the S1 pocket of TACE and those of
the MMPs.13 Modeling analysis has shown that the S1
pocket of TACE tolerates bulkier P1 substituents more
than the S1 subsite of many MMPs. In MMP-13, the
amino acids Ile 159 and Tyr 151 appear to constrict
the S1 pocket, while in TACE the corresponding resi-
dues, Thr 347 and Lys 315, leave a relatively expanded
S1 pocket (Fig. 2).
4
5
6
OH
O
O O2S
O O2S
EtO
EtO
c
d
N
N
Boc
Boc
8
7
O
O
O O2S
O O2S
EtO
EtO
f
e
N
NH
R
10a-s
9
O
O
O O2S
O O2S
HO
HO
N
H
g
h
N
N
R
R
11a-s
12a-s
Scheme 1. Reagents and conditions: (a) (Boc)2O, THF, rt, 2 h, 95%;
(b) LDA, THF, ꢀ78 °C, 3 h, CH2I2, rt, 48 h, 35%; (c) i—4-hydroxy-
thiophenol, K2CO3, DMF (degassed), rt, 3 h; ii—mCPBA, CH2Cl2, rt,
3 h, 70%; (d) 1-bromo-2-butyne, CsCO3, DMF, rt, 1 h, 86%; (e) TFA,
CH2Cl2, rt, 1 h, quant; (f) RCOCl or RSO2Cl, TEA, CH2Cl2, rt, 12 h,
or RCO2H, TBTU/HOBT, TEA, DMF, rt, 12 h, 40–95%; (g) 2 N
LiOH, THF–MeOH, microwave, 100 °C, 300 s, 60–95%; (h)
NH2OHHCl, BOP, DIEA, DMF, 0 °C to rt, 20 h, 60–80%.
Figure 2. Model of a 3,3-piperidine sulfone 12l bounced to TACE
superimposed on MMP13 (green).

H.-G. Lombart et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4333–4337
4335
of 6 with 4-hydroxythiophenol in the presence of K2CO3
gave the corresponding sulfide, which was directly oxi-
dized to sulfone 7 using mCPBA. The butynyloxy P10
moiety was introduced by reaction of hydroxysulfone
7 with 1-bromo-2-butyne in the presence of CsCO3.
The Boc group was subsequently removed with TFA
to provide the key piperidine intermediate 9. Reaction
of 9 with a variety of electrophiles including acid chlo-
rides, sulfonyl chlorides, acids, and carbamates gave a
diverse set of b-sulfone 3,3-piperidine esters 10a–s,
which were converted to the corresponding hydroxamic
acids15 12a–s as illustrated in Scheme 1.
tive, with greater than 300-fold selectivity over MMP-2,
380-fold over MMP-13, and 1100-fold over MMP-14.
TACE potency and selectivity increased with increasing
length of the alkyl chain of the carbamates. In the amide
series, 12e–k, both 12h and 12k show greater than 300-
fold selectivity for TACE over MMP-2, and greater than
1000-fold over MMP-14, with 12k demonstrating sub-
stantial selectivity over MMP-13 as well. The o-tolua-
mide 12h is slightly more active against TACE, and
more selective, than the m- and p-toluamides, 12i and
12j. Sulfonamides 12l, 12m, and 12n, and urea 12o are
also very active inhibitors of TACE, with selectivities
>100-fold against all MMPs screened. Interestingly, the
benzyl sulfonamide derivative 12m has a significantly de-
creased selectivity for TACE over MMP-2 (less than 65-
fold) than the pyridyl analog 12n (175-fold). Isopropyla-
mide 12e and isopropylsulfonamides 12l have similar
selectivities of >100-fold against all MMPs screened.
The analogs were tested in a FRET assay using the cat-
alytic domain of TACE,16 and a subset of analogs were
then profiled for selectivity against MMP-2, -13, and -14
(Table 1). Past efforts from our laboratories indi-
cate9a,d,10b,14 that gaining selectivity over these enzymes
can be challenging, and that selectivity over these MMPs
would be indicative of further broad-spectrum selectiv-
ity. In addition, selected compounds were evaluated
for their ability to inhibit LPS-stimulated TNF produc-
tion in raw cells and in human whole blood (HWB).16
When we compared these results with the selectivity pro-
files exhibited by the analogous 4,4-piperidine sulfone
hydroxamates,12 we were gratified to find that the 3,3-
piperidine series is more selective over MMP-13, validat-
ing our structural analysis. For example, 12b is 14-fold
more selective over MMP-13 than the corresponding
4-piperidine ethyl carbamate (TACE IC50 = 1.4 nM;
MMP-13 IC50 = 16 nM).17 The introduction of bulky
P1 substituents and the optimal placement of these moi-
eties offered by the 3,3-piperidine scaffold have indeed
had a positive effect on selectivity over several MMPs.
As shown in Table 1, compounds 12a–o have excellent
TACE enzyme activity with low nanomolar IC50s that
parallel the activity of the corresponding 4,4-piperidine
sulfone analogs related to 3.12 Only the N-unsubstituted
piperidine analog 12p has a TACE IC50 worse than
15 nM. Also, all of these analogs show greater than
100-fold selectivity for TACE over MMP-13 and -14.
Selectivity over MMP-2 was somewhat lower, with a
range of 40-fold for 12p up to almost 500-fold for o-tol-
uamide 12h. Among the carbamates 12a–d, compound
12c is the most potent against TACE and the most selec-
The activity of compounds 12a–c and 12k was next as-
sessed in raw cells, and moderate potency was observed,
with the most potent being amide 12k (IC50 = 0.3 lM).
However, HWB activity was problematic for the 3,3-
Table 1. In vitro potency of butynyloxyphenyl b-sulfone piperidine hydroxamic acids 12
O
O
S
HO
O
N
H
O
N
R
12
Compound
R
TACEa
MMP-2a
MMP-13a
MMP-14a
Raw Cellsb
HWBc
12a
12b
12c
12d
12e
12f
12g
12h
12i
CO2CH3
14
870
1630
960
1200
1100
1170
2860
1200
1110
840
3440
7440
3410
4160
5640
1460
5650
1860
3020
—
0.87
0.75
1.55
—
34
26
—
—
19
34
17
27
56
28
13
39
37
24
29
—
CO2CH2CH3
CO2CH2CH(CH3)2
CO2C(CH3)3
8.0
3.2
15
2230
840
COCH(CH3)2
COCH(CH3)CH2CH3
CO-Ph
6.3
6.0
5.8
1.7
5.0
8.8
3.0
5.4
4.1
5.9
9.6
62
—
—
520
1140
840
—
—
CO-(2-CH3Ph)
CO-(3-CH3Ph)
CO-(4-CH3Ph)
CO-(4-CH2OCH2CH3-Ph)
SO2CH(CH3)2
SO2CH2Ph
—
1620
760
1010
1370
470
—
—
12j
12k
12l
940
700
3290
5640
1250
1650
—
0.30
—
1190
—
12m
12n
12o
12p
260
—
—
SO2CH2-(4-Pyridyl)
CON(CH2CH3)2
H
1030
—
950
1740
—
—
—
2570
1020
a IC50 (nM).
b Inhibition of LPS-stimulated TNF-a production in Raw Cells, IC50 (lM).
c Inhibition of LPS-stimulated TNF-a production in human whole blood, IC50 (lM).

4336
H.-G. Lombart et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4333–4337
Table 2. In vitro potency of butynylaminophenyl b-sulfone piperidine
hydroxamic acids 13
References and notes
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O
O
S
O
H
N
HO
N
H
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N
R
13
Compound
R
TACEa MMP MMP
HWBb
-2a
-13a
13b
13i
13l
CO2CH2CH3
CO-(3-CH3Ph)
21
8.0
1230
1450
1000
>16,666 38
>16,666 35
>16,666 36
SO2CH(CH3)2 18
a IC50 (nM).
b Inhibition of LPS-stimulated TNF-a production in human whole
blood, IC50 (lM).
piperidine sulfone hydroxamate series of analogs. Thus,
in contrast to the 4,4-piperidine analogs, many of which
have low micromolar IC50s in HWB, the 3,3-piperidine
analogs tested are dramatically less active. For example,
compound 12k is the most potent member of the series
in HWB with an IC50 of 13 lM, and sulfonamide 12l
has an IC50 of 39 lM in HWB, while the corresponding
isopropyl sulfonamide 3 has an IC50 of 1.5 lM.12
6. For a recent review on TACE inhibitors, see: Skotnicki, J.
S.; Levin, J. I. Ann. Rep. Med. Chem. 2003, 38, 153; For
recent publications on TACE inhibitors from other
groups, see: (a) Gilmore, J. L.; King, B. W.; Harris, C.;
Maduskuie, T.; Mercer, S. E.; Liu, R.-Q.; Covington, M.
B.; Qian, M.; Ribadeneria, M. D.; Vaddi, K.; Trzaskos, J.
M.; Newton, R. C.; Decicco, C. P.; Duan, J. J.-W. Bioorg.
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(b) Kamei, N.; Tanaka, T.; Kawai, K.; Miyawaki, K.;
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In a final effort to achieve increased potency and selec-
tivity along with acceptable HWB activity a series of
three 3,3-piperidine sulfone hydroxamates bearing a
butynylamine P10 group were also prepared. Recent
studies have shown that compounds with this P10 moiety
have excellent selectivity over MMP-2 and -13.18 Buty-
nylaminophenyl b-sulfone 3,3-piperidine hydroxamic
acids 13b, 13i, and 13l were prepared by the reaction
of 6 with 4-aminothiophenol and subsequently following
the synthetic route described in Scheme 1. The in vitro
and HWB activities of compounds 13 are listed in Table
2. All of the butynylamine analogs were slightly less ac-
tive in the FRET assay than the corresponding oxygen
analogs (12b, 12i, and 12l), and were somewhat less
selective over MMP-2. However, replacement of the
oxygen atom with a nitrogen atom did significantly
improve the selectivity for TACE over MMP-13 in all
cases, to greater than 800-fold for 13b, and to greater
than 2000-fold for 13i. Unfortunately, the HWB activity
of these compounds was poor.
In summary, using structure-based methods focused on
capitalizing on the shape difference between the S1 pock-
ets of TACE and structurally related MMPs, we have
designed and synthesized a series of b-sulfone 3,3-piper-
idine hydroxamate TACE inhibitors. All of these ana-
logs show excellent, low nanomolar IC50 enzyme
activity in a FRET assay and good selectivity over
MMPs (up to 1100-fold).
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Acknowledgments
We thank Drs. Walter Massefski and Nelson Huang of the
Discovery Analytical Chemistry group for spectral data.
We thank Dr. Katherine Lee for reviewing this manuscript.
8. Renkiewicz, R.; Qiu, L.; Lesch, C.; Un, X.; Devalaraja,
R.; Cody, T.; Kaldjian, E.; Welgus, H.; Baragi, V.
Arthritis Rheum. 2003, 48, 1742.

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using the described synthetic route from ethyl 4-piperidine
carboxylate.
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