Syntheses and in vitro evaluation of arylsulfone-based MMP inhibitors with heterocycle-derived zinc-binding groups (ZBGs)

Article abstract of DOI:10.1016/j.bmcl.2007.10.049

Several classes of arylsulfone-based MMP-2/-9 inhibitors utilizing 6- to 8-membered heterocyclic rings as zinc-binding groups (ZBGs) have been synthesized and their enzyme inhibitory activities were evaluated. Although a number of 6- and 7-membered hetero

Full text of DOI:10.1016/j.bmcl.2007.10.049

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Bioorganic & Medicinal Chemistry Letters 18 (2008) 405–408
Syntheses and in vitro evaluation of arylsulfone-based
MMP inhibitors with heterocycle-derived
zinc-binding groups (ZBGs)
Yue-Mei Zhang,* Xiaodong Fan, Shyh-Ming Yang, Robert H. Scannevin,
Sharon L. Burke, Kenneth J. Rhodes and Paul F. Jackson
East Coast Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development,
Welsh & McKean Roads, Spring House, PA 19477, USA
Received 10 August 2007; revised 30 September 2007; accepted 5 October 2007
Available online 18 October 2007
Abstract—Several classes of arylsulfone-based MMP-2/-9 inhibitors utilizing 6- to 8-membered heterocyclic rings as zinc-binding
groups (ZBGs) have been synthesized and their enzyme inhibitory activities were evaluated. Although a number of 6- and 7-mem-
bered heterocycles were effective, the most potent arylsulfone inhibitors are based on the rigid 1- or 3-hydroxypyridone ZBG.
Ó 2007 Elsevier Ltd. All rights reserved.
Over-expression of matrix metalloproteinases (MMP)
has been implicated in a variety of disease states involv-
ing matrix degradation such as cancer, arthritises, car-
diovascular diseases, and neurological disorders.1
Therefore, MMPs have become valid therapeutic targets
and many MMP inhibitors (MMPIs) have been devel-
oped over the last two decades. However, none of these
compounds has successfully completed clinical trials due
to the lack of efficacy and long-term dose-limiting side
effects in diseases such as cancer and arthritis.2 Despite
these shortcomings, MMP inhibition is still believed to
be a valid therapeutic approach. More recently, it has
been suggested that MMPIs might have efficacy in the
acute clinical setting, in the treatment of disorders such
as ischemic stroke, aneurysm, and myocardial rupture.3
has been reported.4 Recently, hydroxypyridinones (HO-
POs) and pyrones have emerged as novel ZBGs in
MMPI research.5 Previously, we disclosed a novel series
of aryl sulfonamide MMP-2/-9 inhibitors containing
N-hydroxy-2-pyridinone as the ZBG, with excellent
MMP-2/-9 inhibitory activity and in vivo efficacy in a
mouse transient middle cerebral artery occlusion
(tMCAO) model (Fig. 1, 1).6 As part of a continuing ef-
fort to explore heterocycle-based ZBGs in our MMP
program, herein we report the discovery of a novel series
of a- or b-arylsulfone-based MMP-2/-9 inhibitors
containing 6- to 8-membered heterocycles as ZBGs
O
O
MMP-1: >1000 nM
MMP-2: 5.0 nM
MMP-9: 2.4 nM
HO
N
Typically, an active site MMP inhibitor consists of a Zn-
binding group (ZBG) and a recognition motif that binds
to the protein. The vast majority of synthetic MMPIs
generally fall into four classes (categorized by ZBGs):
hydroxamic acids, carboxylic acids, thiols, and tetracy-
clines. To overcome the limitations of these frequently
used ZBGs, the effort to discover other ZBG moieties
N
S
O2
Cl
1
ZBG
O
O
O
O
HO
HO
P1'
O
HO
N
N
H
N
S
O2
m
ZBG
n
4
3
O
n = 1, 5a
n = 2, 5b
n = 3, 5c
2
m = 0, 1
HO
N
Keywords: Matrix metalloproteinase inhibitor; Arylsulfone; MMP-2;
MMP-9; Zinc-binding group.
NH
*
Corresponding author. Tel.: +1 609 409 3498; fax: +1 609 655
6930; e-mail addresses: yzhang5@prdus.jnj.com; xufangymz@
yahoo.com
6
Figure 1. MMPIs with heterocycles as ZBGs.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.049

406
Y.-M. Zhang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 405–408
droxy-2-pyridinone under basic conditions,8 followed
by benzyl cleavage with neat MeSO3H, to give the final
compound 14.
OMe
7
OMe
CHO
c, d
a, b
N
OMs
N
Beyond HOPOs, we also explored non-aromatic hetero-
cyclic ZBGs with the aryl sulfone scaffold. The prepara-
tion of the a-sulfone series with a ‘conformationally
constrained hydroxamic acid’ is outlined in Scheme 3.
Bromo methyl acetate was reacted with aryl thiols, fol-
lowed by ester hydrolysis and peptide coupling with tri-
tyl-protected hydroxylamine, to afford 15. N-Alkylation
of 15 with dibromoalkanes, immediately followed by
mCPBA oxidation and then base treatment of the result-
ing sulfones, gave the cyclized products 16. Again, the
desired P01 groups can be obtained by elaborations of
the R substituent via a variety of synthetic transforma-
tions as described in Scheme 3. Thus, a series of 6- to
8-membered N-hydroxy lactam MMP inhibitors were
synthesized.
O
R
OMe
e,f
when R=F
f
HO
P1'
N
S
O2
O
or
N
S
O2
9
8
Scheme 1. Reagents and conditions: (a) NaBH4, EtOH, ꢀ20 °C, 90%;
(b) MsCl, TEA, CH2Cl2, 87%; (c) (4-R)PhSH, TEA, CHCl3, 50 °C,
84%; (d) UHP/TFAA (2.1:2), CH2Cl2, 0 °C–rt, 54%; (e) (4-OMe)-
PhOH, Cs2CO3, DMF, 90 °C, 78%; (f) 2 N HCl/MeOH (1:1.5), reflux,
96%.
(Fig. 1, 2). These ZBGs (Fig. 1, 3–6) were postulated to
bind the zinc(II) ion in a bidentate fashion.
Synthesis of the N-hydroxy-2-pyridinone-based arylsulf-
one 9 is outlined in Scheme 1. Reduction of 2-methoxy-
3-pyridinecarboxaldehyde with Na BH4 and subsequent
mesylation of the alcohol gave 7. The P01 group was then
installed by an SN2 displacement reaction with an aryl
thiol under basic conditions. Subsequent oxidation with
a urea–H2O2 complex (UHP) and trifluoroacetic anhy-
dride afforded the fully oxidizded compound 8. The R
substituent can be further elaborated via nucleophilic
aromatic displacement of fluorine to obtain a biaryl
ether P01 substituent. The hydrolysis of the 2-methoxy-
pyridine N-oxide provided the target compound 9 in
high yield.
Compound 20 containing 1-hydroxy-[1,4]-diazepin-2-
one as a ZBG was synthesized according to the sequence
detailed in Scheme 4. (S)-N-Boc-2-amino-3-hydroxypro-
pionate was converted to the corresponding tosylate and
subsequent displacement with an aryl thiol gave 18.
Methyl ester 18 was then converted into trityl-protected
hydroxamate 19 via a hydrolysis-peptide coupling se-
quence. Bis-alkylation of 19 under basic conditions fol-
lowed by sulfide oxidation and trityl de-protection
afforded target molecule 20.
Similarly, Scheme 2 describes the preparation of com-
pounds containing a 3-hydroxy-2-pyridinone ZBG.
Chloromethylsulfone 11 was obtained via a one-pot
two-step sequence from commercially available sulfonyl
chloride 10 and bromochloromethane.7 Pd-catalyzed
Suzuki coupling or Cu(I)-catalyzed Ullmann coupling
with an aryl bromide, or alternatively SN2 displacement
of an aryl fluoride with an appropriately substituted
phenoxide, afforded 12. The Suzuki or Ullmann cou-
pling needed to be monitored closely as prolonged reac-
tion time increased the formation of the by-product
methyl sulfones resulting from chloride reduction. Com-
pound 12 was then reacted with benzyl protected 3-hy-
O
Ph
Ph
d, e, f
a,b,c
O
S
R
Br
N
MeO2C
HN
Ph
15
O
O
O2
S
O2
S
Ph
Ph
g, h
HO
P1'
O
R
N
Ph
n
n=1,2,3
n
17
16
Scheme 3. Reagents and conditions: (a) (4-X)PhSH, TEA, THF,
reflux, 90%; (b) KOH, MeOH/H2O, 95%; (c) O-trityl-hydroxylamine,
EDCI, NMP, HOBt, DMF, rt, 84%; (d) BrCH2(CH2)nCH2Br,
Cs2CO3, DMF, rt, 65%; (e) mCPBA, CH2Cl2, rt, 67%; (f) Cs2CO3,
THF, 60 °C, 60%; (g) when X = F, ArOH, K2CO3, DMF, 100 °C, 69–
30%; when X = Br, 5 mol% Pd(PPh3)4, aq Na2CO3 (2 M), 1,4-dioxane,
78%; (h) TFA/CH2Cl2 (1:1), rt, 87%.
Ar'
Ar-z
Cl
Cl
Ar(4-X)
a,b
c or d
S
S
Ar(4-X)
Cl
S
O2
O2
O2
O
O
z: bond, O
11
c,d
10
a,b
P1'
O
12
MeO
OH
NHBoc
MeO
S
O
O
NHBoc
e
HO
P1'
f
BnO
P1'
N
S
O2
18
N
S
O2
Bn
O
O
O
NH
HO
P1'
14
P1': --Ar-z-Ar'
e, f, g
Ph
Ph
O
P1'
13
N
S
O2
N
H
S
NHBoc
NH
Ph
Scheme 2. Reagents and conditions: (a) Na2SO3, NaHCO3/H2O; (b)
BrCH2Cl, TBAB (cat.), 60% (two step); (c) when X = Br, 1.2 equiv
Ar0B(OH)2, 5 mol% Pd(dppf)Cl2, 2.0 equiv Na2CO3 (2 M), 1,4-
dioxane/H2O, 74%; (d) when X = F, 1.1 equiv Ar0OH, K2CO3,
DMF, 88%; when X = Br, 1.3 equiv. Ar0OH, 10 mol% CuI, 40 mol%
2,2,6,6-tetramethyl-heptane-3,5-dione, Cs2CO3, DMF, 100 °C, 66%;
(e) Cs2CO3, DMF, 85%; (f) MeSO3H, 15 min, 90%.
19
20
Scheme 4. Reagents and conditions: (a) TsCl, pyridine, CH2Cl2, 0 °C–
rt, 85%; (b) HS-P10, K2CO3, DMF, rt, 85%; (c) LiOH, THF/H2O,
0 °C–rt, 96%; (d) EDC, HOBt, DMAP, TEA, Ph3CONH2, CHCl3, rt,
70%; (e) I(CH2)3Cl, Cs2CO3, DMF/MeCN, then NaH, 19%; (f)
mCPBA, CH2Cl2, rt, 84%; (g) TFA, Et2O, rt, 74%.

Y.-M. Zhang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 405–408
Table 1. IC50 (nM) values and SAR of compounds 9, 14, 17, and 20
407
O
P1'
O
H
S
O2
m
ZBG
Compound
ZBG
m
P10
MMP-2 (nM)a
>1000
MMP-9 (nM)a
9a
3
1
>1000
7.3
O
O
9b
3
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
1
17.2
468
OMe
14a
14b
14c
14d
14e
14f
14g
14h
17a
17b
17c
17d
17e
17f
20
4
809
4
16.7
12.6
84.5
10.6
>1000
184
45.8
4.0
O
O
O
O
4
OCF3
OMe
Cl
4
56.1
16.4
>1000
522
4
4
OMe
OMe
4
S
S
OMe
O
4
72.0
167.5
95.9
59.4
377
13.9
87.9
31.0
21.5
846
5a
5b
5b
5b
5b
5c
6
O
O
O
OMe
OMe
OCF3
HN
F
N
>1000
>1000
36.8
>1000
>1000
21.1
OMe
O
O
OMe
a Values are means of at least two experiments.
All compounds were tested against the MMP-2 and
MMP-9 enzymes and the inhibitory activities are sum-
marized in Table 1. Generally, the compounds with
more rigid HOPOs (3 and 4) as ZBGs were preferred.
Both compounds 9b and 14c exhibited single digit
nanomolar IC50s against MMP-9. Nevertheless, the 7-
membered heterocycles, N-hydroxy-azepin-2-one and
N-hydroxy-[1,4]-diazepin-2-one, were also found to be
effective ZBGs (17b–c and 20). These heterocycles have
not been reported as ZBGs in the design of MMPI.
Compound 17c with a a-sulfone scaffold and compound
20 with a b-sulfone scaffold showed comparable MMP-9
activity. This demonstrates the versatility of the N-hy-
droxy-lactam functionality as a ZBG in MMPIs with

408
Y.-M. Zhang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 405–408
a
Table 2. IC50 values against selected MMPs of 9b, 14c, and 20
the introduction of a P1 group on the cyclic ZBGs are
underway. The compounds disclosed here along with
the reported MMP inhibitors containing HOPOs and
hydroxypyrones5 as the ZBGs suggest a new direction
for the design of novel ZBGs and MMPIs with im-
proved physico-chemical properties and selectivity.
Compound MMP-1 MMP-2 MMP-3 MMP-9 MMP-13
9b
>1000
>1000
>1000
17.2
12.6
36.8
308
203
964
7.3
4.0
13.4
7.3
14c
20
21.1
11.0
a IC50 (nM) values are means of at least two determinations.
different scaffolds. Although docking of compound 14c
in an MMP-9 homology model indicates that one of
the sulfonyl oxygen atoms forms a H-bond with the
backbone –NH of Leu 188, it is unclear whether the cor-
responding sulfonyl oxygen of 17c or 20 interacts with
the peptide backbone of MMP-9 in a similar fashion.
Replacing the N-hydroxy-azepin-2-one moiety of 17b
with the smaller N-hydroxy-piperidin-2-one of 17a let
to a threefold decrease in inhibitory potency against
MMP-9 and a twofold decrease against MMP-2. Sur-
prisingly, the 8-membered N-hydroxy-azocin-2-one
ZBG (17f) was not tolerated. This observation suggests
that the size of the N-hydroxy-lactam has a significant
impact on the optimal-binding mode of the molecules.
Table 1 also reveals that the size and geometry of the
P01 group is critical for MMP-2/-9 inhibitory activities.
In particular, compounds 9a and 14a with shorter P10
substituents do not exhibit good inhibitory activity. A
larger P01 group is necessary to reach the deeper S01 pock-
ets of MMP-2 and -9. However, the linear biaryl P10
groups do not fit well into the S01 subsite (14f and 17e).
This agrees with our previous observation in the 1,2-
HOPO-based sulfonamide series (Fig. 1, 1).6 Further-
more, some inhibitory activity can be recovered by
incorporating an angled P01 group containing 5-mem-
bered heteroaromatic rings, as in compounds 14g and
17d. Compounds 9b, 14c, and 20 were screened against
other MMPs (Table 2) and showed excellent selectivity
over MMP-1 and 40- to 50-fold selectivity over
MMP-3. These compounds are also potent inhibitors
of MMP-13.
Acknowledgment
The authors thank Dr. Mark J. Macielag for the kind
review and helpful comments.
Supplementary data
Synthetic details of all compounds in Table 1. Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.bmcl.2007.10.049.
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In summary, we discovered several classes of MMP
inhibitors containing heterocyclic ZBGs which showed
good inhibitory activities against the MMP-2 and -9 en-
zymes and excellent selectivity over MMP-1. Further
structural modifications of these MMPIs to pick up
additional-binding interactions with the enzyme through