Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid inhibitors of matrix metalloproteinase-13

Article abstract of DOI:10.1016/j.bmcl.2011.08.087

The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would provide a disease modifying therapy for the treatment of arthritis, although this goal still continues to elude the pharmaceutical industry due to issues with safety. Our efforts have resulted in the discovery of a series of hydroxamic acid inhibitors of MMP-13 that do not significantly inhibit MMP-2 (gelatinase-1). MMP-2 has been implicated in the musculoskeletal side effects resulting from pan-MMP inhibition due to findings from spontaneously occurring human MMP-2 deletions. Analysis of the SAR of hundreds of previously prepared hydroxamate based MMP inhibitors lead us to 2-naphthylsulfonamide substituted hydroxamates which e hibited modest selectivity for MMP-13 versus MMP-2. This Letter describes the lead optimization of 1 and identification of inhibitors exhibiting >100-fold selectivity for MMP-13 over MMP-2.

Full text of DOI:10.1016/j.bmcl.2011.08.087

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6440–6445
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid
inhibitors of matrix metalloproteinase-13
Ruben A. Tommasi, Sven Weiler, Leslie W. McQuire, Olivier Rogel, Mark Chambers, Kirk Clark,
John Doughty, James Fang, Vishwas Ganu, Jonathan Grob, Ronald Goldberg, Robert Goldstein,
Stacey LaVoie, Raviraj Kulathila, William Macchia, Richard Melton, Clayton Springer, Marc Walker,
⇑
Jing Zhang, Lijuan Zhu, Michael Shultz
Novartis Institutes for Biomedical Research, Inc., Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in
cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would provide a disease modi-
fying therapy for the treatment of arthritis, although this goal still continues to elude the pharmaceutical
industry due to issues with safety. Our efforts have resulted in the discovery of a series of hydroxamic
acid inhibitors of MMP-13 that do not significantly inhibit MMP-2 (gelatinase-1). MMP-2 has been impli-
cated in the musculoskeletal side effects resulting from pan-MMP inhibition due to findings from spon-
taneously occurring human MMP-2 deletions. Analysis of the SAR of hundreds of previously prepared
hydroxamate based MMP inhibitors lead us to 2-naphthylsulfonamide substituted hydroxamates which
exhibited modest selectivity for MMP-13 versus MMP-2. This Letter describes the lead optimization of 1
and identification of inhibitors exhibiting >100-fold selectivity for MMP-13 over MMP-2
Ó 2011 Elsevier Ltd. All rights reserved.
Received 3 June 2011
Revised 17 August 2011
Available online 27 August 2011
Keywords:
Metalloproteinase
Hydroxamic acids
Enzyme inhibitor
Arthritis
The matrix metalloproteinase (MMPs) are unregulated in osteo-
arthritis (OA) and are largely responsible for the destruction of col-
lagens and proteoglycans in cartilage and bone, leading to loss of
joint function in this disease. MMP-13 is the primary enzyme
which cleaves type II collagen and thus, inhibition of this enzyme
is viewed as one of the most promising approaches to the treat-
ment of cartilage degradation in arthritis. There have been many
efforts to target MMPs as therapeutic approaches,1 predominantly
using broad-based hydroxamic acid inhibitors, which have been
hampered due primarily to musculoskeletal side effects, the exact
nature is still uncertain.2,3 The cause of these side effects has been
significantly debated and one hypothesis that we were concerned
with was a possible link to MMP-2 inhibition. MMP-2’s role in
causing musculoskeletal side effects was implicated by familial
genetic studies reported by Martignetti et al.4
MMP-1 could exploit the smaller S10 pocket in this enzyme.5 How-
ever, MMP-2 has a very similar S10 channel to MMP-13 as do most
other MMPs. Thus, the identification of MMP-13 inhibitors sparing
these other isoenzymes would require taking advantage of more
subtle differences in the active sites. During the course of this work,
the feasibility of achieving selectivity between these enzymes has
been demonstrated by several groups. Hydroxamic acid derived
inhibitors of MMP-13 sparing other family members have been
reported by Barta and coworkers.6–11 Also, several series of specific,
non-zinc-binding MMP-13 inhibitors have also been identified.12,13
Our efforts were initiated by analyzing the vast SAR established
from our previous approaches towards MMP-13 inhibitors.5,14
Most of the compounds we examined exhibited little or no selec-
tivity for MMP-13 over MMP-2. Figure 2 illustrates the correlation
for MMP-13 and MMP-2 activity for the MMP inhibitors from these
previous efforts. The activity trend between the two enzymes is
easy to see and relatively few compounds exhibited 10-fold selec-
tivity for MMP-13. Through this analysis, we noticed that the
2-naphthyl sulfonamide substituted inhibitor 1, exhibited modest
selectivity (ꢀ10-fold).
Given these findings, we set out to identify selective MMP-13
inhibitors with respect to MMP-2. Given the similarity of these
enzymes (60% homology; 100% at the active site), as illustrated in
Figure 1, we viewed this as a formidable task when we initiated
these efforts. Earlier studies towards compounds that spared
Interestingly, this modest selectivity was sensitive to the pres-
ence of a substituent on the sulfonamide nitrogen as exemplified
by comparing 1 and 2 as illustrated in Figure 3. This effect was sur-
prising given that we expected the N-alkyl substituents to point into
solvent based on our previous experience with CGS027023.14 This
Abbreviations: MMPs, matrix metalloproteases; OA, osteoarthritis; IA,
intra-articular.
⇑
Corresponding author.
E-mail address: michael.shultz@novartis.com (M. Shultz).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.087

R. A. Tommasi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6440–6445
6441
N
O
O
O
O
S
HO
N
HO
N
N
H
S
N
H
O
O
O
1
CGS027023
MMP-13: 1.2 nM
MMP-2: 2.0 nM
ratio 2/13: 1.7
MMP-13: 8 nM
MMP-2: 86 nM
ratio 2/13: 10
O
O
H
O
H
O
HO
N
S
HO
N
N
H
N
H
S
O
O
2
9
MMP-13: 180 nM
MMP-2: 163 nM
ratio 2/13: ~1
MMP-13: 33 nM
MMP-2: 96 nM
ratio 2/13: ~3
Figure 3. Structure, activity and selectivity of initial naphthyl hydroxamate leads in
comparison to CGS027023.
Figure 1. Sequence differences between MMP-13 (magenta) and MMP-2 (green) in
the S10 binding region. The colored ribbons represent the path of the backbone
atoms for both proteins. The catalytic Zinc for the MMP-13 structure is shown and
labeled ‘ZN2’. Where the sequences differ between the proteins, the residue atoms
and name is given. The white surface depicts the binding cleft and entry into the S10
pocket. MMP-13 has three residues that are not resolved in the crystal structure,
which are represented with three dashes in the ribbon and the three letter codes for
the amino acid residues.
X
X
O
O
R2
N
R
NH2
a, b
R
O
+
O
S
O
R1
S
O O
R1
O
3
Cl
4
5
c or d
X
X
O
R2
N
O
R2
N
e, f
HO
N
H
S
HO
S
O O
O O
R1
R1
7
6
Scheme 1. General route to naphthylsulfonamide substituted hydroxamates.
Reagents: (a) Et3N, CH2Cl2; (b) R2-I, K2CO3, DMF; (c) HCl, EtOAc; (d) H2, 10% Pd/C,
EtOAc; (e) O-trityl-hydroxylamine, NMM, HOAt, EDCI, CH2Cl2; (f) TFA, Et3SiH,
CH2Cl2.
O
OAc
a, b
O
R2
N
R3
O
R2
N
O
R
S
O
O
R
S
O
O
O
R1
R1
8
6a
Scheme 2. Routes to 6-substituted naphthylsulfonamide analogs. Reagents: (a)
K2CO3, EtOH/water; (b) R3-I, K2CO3, DMF.
Figure 2. Summary of selectivity for MMP-13 overMMP-2 for our collection of
MMP inhibitors.1 is highlighted by the circle as one of the compounds exhibiting
modest selectivity.
with tritylhydroxylamine afforded the trityl protected hydroxa-
mates which were deprotected by the action of TFA and triethylsi-
lane in dichloromethane. Alternatively, amino acid benzyl esters
(3, R = Bn) could be used as starting materials as this also allowed
mild ester deprotection. Thus, after similar sulfonylation and alkyl-
ation, deprotection of the benzyl esters by hydrogenolysis using
10% Pd/C in EtOAc afforded 6 in excellent yields.
Synthesis of the 6- and 7-alkoxy substituted naphthyl analogs
was accomplished via preparation of the acetoxy intermediate
6a under conditions described above starting from the commer-
cially available acetoxy-naphthyl sulfonyl chlorides. As shown in
Scheme 2, the 6-acetoxy group was hydrolyzed in ethanol/water
to yield the phenol, which was converted to alkyl ethers, 8, via
alkylation mediated by K2CO3 in DMF. Conversion of 8 to the
desired hydroxamic acid derivates was accomplished as described
above in Scheme 1. Preparation of the desired 7-alkoxy substituted
analogs was affected in an analogous manner from the commer-
cially available 7-acetoxy naphthyl sulfonyl chloride.
effect is not observed in the absence of the naphthyl sulfonamide as
various other hydroxamates (including CGS027023) were in this
screening set (data not shown). It appeared to us that both the naph-
thyl and the N-substituent were required to achieve enzyme selec-
tivity. Thus, we set out to better understand this effect and
determine whether improvement was possible. Herein we report
the optimization of 1 which has lead to the discovery of potent
MMP-13 inhibitors with >100-fold selectivity over MMP-2.
A general route to naphthyl substituted hydroxamates was uti-
lized in analogous fashion to work we have reported previously.8,14
as illustrated in Scheme 1. Sulfonylation of amino acid ester, 3
(R = tBu), followed by N-alkylation yielded the t-butyl sulfonamide
ester 5 in good yields, however the rate of reaction diminished
with increasing steric bulk of the alpha substituent. Removal of
the t-butyl ester by the action of HCl in EtOAc followed by coupling

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R. A. Tommasi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6440–6445
Table 1
N-Alkyl substituted naphthyl hydroxamates
O
R2
N
HO
N
H
S
O O
Compound
R2
IC50 (nM)
Ratio (MMP-2/-13)
MMP-13
MMP-2
9
10
H
Me
33
2.9
96
54
2.9
18
11
12
7
308
384
44
*
*
3.0
128
Ph
13
14
28
706
200
25
Figure 4. X-ray crystal structure of 12 in MMP-13. The protease domain of MMP-13
was co-crystallized with compound 12 and the x-ray structure was determined to a
resolution 1.3 Angstroms. The napthyl group is in the S10 pocket, the hydroxamate
is chelating the catalytic Zn (yellow sphere) and a sulfonamide oxygen is forming a
hydrogen with the protein backbone across from the S10 pocket (behind the valine
in the foreground). Coordinates and X-ray data for this structure are available from
the Protein Data Bank, deposition code 3zxh.
*
Ph
Ph
2.0
100
*
15
24
798
33
*
*
*
*
N
N
and 14 in Table 1, which achieve greater than 100-fold selectivity
for MMP-13 over MMP-2. It is noteworthy that polar substituents,
as in entries 19 and 20, are disfavored by both enzymes. An inter-
esting exception to this however, is the o-pyridyl analog 18, which
maintains good selectivity due to its potent MMP-13 activity. It
was also observed that the m-pyridyl analog 17, which contains
the identical N-alkyl modification as CGS27023, was the most po-
tent MMP-2 inhibitor and the least selective analog in this subset
of compounds.
In order to better understand the observed selectivity, the co-
crystal structure of 12 in MMP-13 was solved (Fig. 4). As predicted
from other structures, the N-substituents are solvent exposed and
not in proximity to residues that differ in MMP-13 and MMP-2. We
consider it most likely that the intrinsic flexibility of these S10
pockets differ. The S10 pockets in MMP-13 and MMP-2 are more
accurately described as tunnels. The ‘bottom’ of the pocket is fully
solvent exposed and able to accommodate very large, extended
molecules. The top of these pockets, as illustrated in Figure 1, are
formed by an extended loop. A deletion in the amino acid sequence
of MMP-2 relative to MMP-13 near the bottom of the S10 pocket
may contribute to changes in flexibility. The hydroxamate’s inter-
actions with the catalytic Zn, and the sulfonamide’s interactions
with the backbone of the protein rigidify or ‘lock-in’ the position-
ing of the core scaffold and contribute greatly to the binding en-
ergy. Increasing the rigidity of the scaffold favors MMP-13 which
appears to be better able to adapt to the naphthyl substituent. This
trend has been observed in other studies15 based on different
scaffolds.
16
17
18
19
7
200
25
28
15
2.2
32
1.7
116
19
232
607
N
N
*
*
O
N
20
18
144
8
Our initial exploration of the selectivity observed with 2 was
centered around understanding the impact of the N-substituent
on selectivity. Toward this end, we prepared a variety of analogs
with relatively large substituents as well as analogs containing
water solublizing groups at this position. The results of these stud-
ies are summarized in Table 1 where assays were performed as
previously described.5 Interestingly, the selectivity for MMP-13
versus MMP-2 is very dependent on the nature of the N-substitu-
ent and appears driven by effects on both enzymes. Generally,
the N-substituent has a beneficial effect on MMP-13 activity as
exemplified by the 10-fold improvement in MMP-13 activity for
entry 10 in comparison with 9. In this particular case, MMP-2
activity is only two-fold improved for 10. As the size of the alkyl
substituent increases, however, there is a slight drop in the
MMP-2 activity. When combined, these effects can result in a
marked improvement in selectivity as illustrated with entries 12
Beyond the selectivity gain from having an N-substituent, there
are clearly additional effects from the nature of substituent. We
observe favorable hydrophobic interactions between aliphatic sub-
stituent of compound 12 and Pro242 in MMP-13; however, in the
absence of high-resolution co-crystal structures of MMP-2, it is dif-
ficult to fully understand which interactions with MMP-2 may
influence the selectivity of the compounds. Nonetheless, a few
interesting features stand out including the sensitivity of the pyri-
dyl N position in selectivity. The 4-pyridyl analog 16 increases po-
tency for both MMP-2 and -13 to a similar degree with nearly
identical selectivity as 13. Replacement with 3-pyridyl (14), the

R. A. Tommasi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6440–6445
6443
Table 2
Table 3
Amino acid variations
6- and 7-alkoxy substituted naphthyl sulfonamides
O
O
R3
HO
N
HO
N
N
H
S
N
H
S
O
O
O O
R1
Compound
R1
IC50 (nM)
Ratio (MMP-2/-13)
Compound
R3
H
6-OH
7-OH
6-OMe
7-OMe
6-OEt
7-OEt
6-O-nPr
6-O-iBu
IC50 (nM)
Ratio (MMP-2/-13)
MMP-13
MMP-2
MMP-13
MMP-2
*
12
29
30
31
32
33
34
35
36
37
38
39
3
1
384
178
3286
180
4370
307
9200
197
102
931
1610
45
128
178
13.6
138
9.1
85
15
20
7.8
5.3
9.8
150
12
21
3.0
384
128
213
242
1.3
480
3.6
603
10
*
0.6
1.3
128
83
*
22
23
66
7
13
HO
*
6-O-iAmyl
6-OBn
6-Et
176
165
0.3
12
26
28
81
458
706
O
*
activity with the t-leucine analog in both enzymes suggests it ste-
rically hinders the ligand from adopting its bound conformation.
While modification of the amino acid could play a role in optimiz-
ing ADME properties of the molecule, we did not find analogs that
stood out as being superior to the valine derived analog 12.
Further optimization centered around deeper exploration into
the S10 site via naphthyl substitutions. As depicted in Table 3, our
focus was still on 12 as a benchmark for this comparison and we
set out to evaluate the effect of 6- and 7-substitution on the naph-
thyl group. Based on the crystal structure of 12 in MMP-13, we de-
emphasized substitution at the other naphthyl positions given that
there is no space in the S10 channel to accept these substitutions.
Small substituents were in fact explored, but these analogs exhib-
ited significantly less activity (data not shown). The SAR estab-
lished with the 6- and 7-alkoxy substituted analogs clearly
indicates a preference for the 6-substituted analogs. Thus, further
optimization focused solely on substitution at the 6-position. Sur-
prisingly, given the size of the S10 pocket, large substituents at the
6-naphthyl position lead to loss of MMP-13 activity as exemplified
by entries 35–38. While small alkyloxy groups are well tolerated,
n-propyl and i-butyl substitution results in analogs with 10 nM
or greater IC50. Moreover, the effect of these changes on MMP-2
appears less significant (e.g., entry 31 vs 35 indicates no effect on
MMP-2 while a 10-fold loss on MMP-13). Further increases in size
(isoamyl or benzyl, entries 37 and 38, respectively) reduced
potency against MMP-13. A methoxy to ethyl isosteric replacement
(39) results in increased potency of approximately four-fold with
no change in selectivity. It is evident from these examples, that
there is a relatively narrow margin to work with in this system
to achieve acceptable potency for MMP-13 while maintaining suit-
able (>100-fold) selectivity versus MMP-2.
24
25
18
25
Ph
*
OH
*
26
2.2
200
100
O
*
27
28
34
3670
111
108
37
*
3.2
OH
same N-alkyl substituent as CGS27023, results in a compound with
equal selectivity as the latter compound, and with similar potency
as 13. The 2-pyridyl analog 18 was essentially unchanged from 12
in terms of potency and selectivity, but with a
D
c log P of ꢁ1.8.
Given our results with analogs depicted in Table 1, we chose the
N-isoamyl analog (12) as a benchmark for further study. We then
focused our attention on the amino acid substituent. As illustrated
in Table 2 both MMP-2 and MMP-13 are rather tolerant of a variety
of alpha substituents on the amino acid moiety. The switch from
valine to leucine (compound 21) improved potency against both
MMP-13 and -2, with a slight improvement in selectivity. It was
known from previous efforts, however, that hydroxamic acids
become more susceptible to enzymatic hydrolysis in vivo when
b-substitution was decreased so the overall benefit of 21 is
assumed less than the in vitro data might suggest. We were some-
what surprised by the 10-fold loss of MMP-13 activity of entries 24
and 25. Inspection of the crystal structure of MMP-13 does not
shed light on the reason for this loss of activity. We found the t-leu-
cine analog, 27, to be particularly interesting given the MMP-2
activity was driven into the micromolar range for the first time.
Unfortunately, a similar 10-fold loss in MMP-13 activity resulted
with this analog. The N-alkyl and amino acid variants are in prox-
imity to each-other when bound to the protein. The uniform loss of
We sought to improve the properties of compound 12 including
the moderately high lipophilicity (c log P = 4.4) and low solubility
(<5 lM at pH 6.8) by seeking a heterocycle isostere of the naphthyl
ring. Several quinoline and isoquinoline derivatives (40–42) were
made and demonstrate a high degree of sensitivity in the S10 pock-
et. Absolute potency increased from napthyl to benzothiophene
(43), dihydrobenzofuran (44) and dihydrobenzo[1,4]dioxane (45),
however all modifications resulted in diminished selectivity rela-
tive to 12. The need for a fused ring system is highlighted in the
poor activity of 46.
Based on these findings, several analogs were selected for fur-
ther profiling which included rat pharmacokinetics, evaluation in

6444
R. A. Tommasi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6440–6445
Table 5
cartilage chip assays, as well as efficacy in a rat intra-articular
injection model. We first examined the rat pharmacokinetic profile
via cassette dosing of selected compounds (Table 5) at 5 mg/kg po
and 1 mg/kg iv. In rats, compound 12 had moderate in vivo clear-
ance (2.4 L/h/kg), t1/2 of 5.7 h, and marginal oral bioavailability
Rat PK (cassette dosing) of selected compounds
Compound
MMP-13
IC50 (nM)
CL
(L/h/
kg)
AUCpo
M h)
AUCpo/
MMP-13 IC50 (h)
(
l
LipE
12
14
16
17
19
22
27
28
40
42
43
3
2
4.1
4.4
5.6
5.2
4.6
6.4
2.9
5.8
3.7
5.0
4.5
2.4
3.3
7.3
6.4
14
2.7
1.6
3.3
5.5
1.1
7.1
1.5
406
224
46
42
8
1993
209
1001
1.3
380
844
(F = 23.8%) with oral exposure of 1.5 lM h. Hydroxamates typically
0.45
0.32
0.55
0.27
2.4
7.2
3.1
0.13
4.6
1.5
suffer from enzymatic hydrolysis in vivo and we sought to find
modifications that could decrease clearance, improve oral expo-
sure relative to MMP-13 potency while retaining selectivity against
MMP-2.16 To better evaluate compounds, we looked at oral expo-
sure as a function of MMP-13 activity and later analyzed the data
to determine if a composite parameter analysis (e.g., lipophilic effi-
ciency or LipE) would help us simplify the complex number of vari-
ables involved in achieving this goal.
6.8
15
32
1.3
34
3.2
100
12
1.8
As a group, the N-alkyl derivatives were wholly devoid of any
improvement to clearance or oral exposure. Compounds 14, 16,
17 and 19 all had higher clearance and lower oral exposure, likely
due to first pass metabolism, relative to 12. We hypothesize that N-
dealkylation may contribute to clearance in vivo and the isoamyl
modification appears to have the best balance of potency, selectiv-
ity and metabolic stability.
Modification of the amino acid moiety had a more dramatic ef-
fect on oral exposure as compounds 22, 27 and 28 all had similar or
greater oral exposure relative to 12 that does not appear attribut-
able to reduced clearance. It is interesting to note that the hydroxy
modifications essentially have no effect on MMP-13 potency, but
have greater lipophilic efficiency than the corresponding alkyl
derivatives (e.g., 28 vs 12). The serine and threonine based com-
pounds have the highest LipE and the highest oral exposure rela-
tive to MMP-13 potency. Unfortunately, their LipE is even greater
for MMP-2 as manifest by lower selectivity.
Rat cassette PK following oral (5 mg/kg) and intravenous (1 mg/kg) dosing in 20%
Replacement of the naphthyl moiety by various heterocycles
was intended to reduce oxidative metabolism (Table 4), however
only the quinoline derivative 42 appeared to achieve this goal.
The reduced in vivo clearance and higher oral exposure was unfor-
tunately offset by a similar decrease in MMP-13 potency and selec-
tivity against MMP-2.
Most of the analogs we explored failed to significantly exhibit
cartilage protection in the bovine articular cartilage chip assay. In
the rat injection model, we were also unable to demonstrate carti-
lage protection (data not shown for both experiments). Presum-
ably, the loss of activity in the tissue and in vivo assays are due
to poor physical properties in the series stemming from incorpora-
tion of the naphthyl group. Unfortunately, polar N-substitution
which was successful in the optimization of CGS027023 was not
successful in this case due to loss of potency on MMP-13 as well
as selectivity versus MMP-2. The PK results from various modifica-
tions helped reprioritize areas for modification and helped deter-
mine some of the inherent limitations of this scaffold and
advanced our understanding of how to design selective MMP-13
inhibitors. Due to these challenges, optimization of this series
was terminated and efforts were focused on cyclic amino acid ana-
logs as well as smaller naphthyl replacements. The results of those
studies will be reported in due course.
Table 4
Heterocyclic sulfonamide and naphthyl sulfonamide isosteres
O
R3
HO
N
N
H
S
O O
Compound
R4
IC50 (nM)
Ratio (MMP-2/-13)
Acknowledgments
MMP-13
3
MMP-13
384
The authors would like to dedicate this paper to the memory of
our beloved colleague Olivier Rogel. The authors thank Dr. Dennis
Roland for many years of support and guidance on this project.
12
40
128
21
*
*
100
361
2050
6913
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N
N
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41
42
19
26
*
N
12
306
*
*
*
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