Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD)

Article abstract of DOI:10.1016/j.bmcl.2011.11.046

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with irreversible progressive airflow limitation. Matrix metalloproteinase-12 (MMP-12) has been characterized to be one of the major proteolytic enzymes to induce airway remodeling, destruction of elastin and the aberrant remodeling of damaged alveoli in COPD and asthma. The goal of this project is to develop and identify an orally potent and selective small molecule inhibitor of MMP-12 for treatment of COPD and asthma. Syntheses and structure-activity relationship (SAR) studies of a series of dibenzofuran (DBF) sulfonamides as MMP-12 inhibitors are described. Potent inhibitors of MMP-12 with excellent selectivity against other MMPs were identified. Compound 26 (MMP118), which exhibits excellent oral efficacy in the MMP-12 induced ear-swelling inflammation and lung inflammation mouse models, had been successfully advanced into Development Track status.

Full text of DOI:10.1016/j.bmcl.2011.11.046

Bioorganic & Medicinal Chemistry Letters 22 (2012) 138–143
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of potent and selective matrix metalloprotease 12 inhibitors
for the potential treatment of chronic obstructive pulmonary disease (COPD)
Yuchuan Wu a, , Jianchang Li a, Junjun Wu a, Paul Morgan a, Xin Xu a, Fabio Rancati b, Stefania Vallese b,
⇑
Luca Raveglia b, Rajeev Hotchandani a, Nathan Fuller a, Joel Bard a, Kristina Cunningham a, Susan Fish a,
Rustem Krykbaev a, Steve Tam a, Samuel J. Goldman a, Cara Williams a, Tarek S. Mansour a, Eddine Saiah a,
Joseph Sypek a, Wei Li a
a Pfizer Global Research & Development, 200 CambridgePark Drive, Cambridge, MA 02140, USA
b NiKem Research S.r.L., Via Zambeletti 25, 20021 Baranzate, MI, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with irrevers-
ible progressive airflow limitation. Matrix metalloproteinase-12 (MMP-12) has been characterized to be
one of the major proteolytic enzymes to induce airway remodeling, destruction of elastin and the aber-
rant remodeling of damaged alveoli in COPD and asthma. The goal of this project is to develop and iden-
tify an orally potent and selective small molecule inhibitor of MMP-12 for treatment of COPD and asthma.
Syntheses and structure–activity relationship (SAR) studies of a series of dibenzofuran (DBF) sulfona-
mides as MMP-12 inhibitors are described. Potent inhibitors of MMP-12 with excellent selectivity against
other MMPs were identified. Compound 26 (MMP118), which exhibits excellent oral efficacy in the MMP-
12 induced ear-swelling inflammation and lung inflammation mouse models, had been successfully
advanced into Development Track status.
Received 25 September 2011
Revised 9 November 2011
Accepted 14 November 2011
Available online 20 November 2011
Keywords:
MMP-12
COPD
SAR
Dibenzofuran
Ó 2011 Elsevier Ltd. All rights reserved.
Chronic obstructive pulmonary disease (COPD) is an inflamma-
tory lung disease which is characterized by a progressive airflow
limitation and associated with an abnormal inflammatory response
of the lungs to noxious particles or gases, mainly caused by cigarette
smoke.1,2 This disease affects ꢀ16 million people in the US alone3
and ranks among the top five leading causes of death worldwide,
and it is estimated that it will be in the mortality top three by 2020.4
The matrix metalloproteinases (MMPs) are a protein family of
zinc dependent endopeptidases which can degrade a variety of ma-
trix components in both normal physiological states and in abnor-
mal pathological process. They are mainly involved in extracellular
cleavage and play important roles in diverse biological and espe-
cially pathological process such as inflammation, fibrosis and can-
cer.5 Increased MMP expression in COPD development has been
demonstrated in animal studies and preliminary studies in hu-
mans. However, the poor outcomes observed in preclinical studies
using broad spectrum inhibitors of MMPs6 suggest the need for
MMP inhibitors with better selectivity profile. Recently, there is
increasing experimental evidence indicating that some lung dis-
eases such as COPD, asthma and lung cancers are associated with
MMP-12 mediated pathologic degradation.7 MMP-12 is mainly
produced by macrophage and involved in acute and chronic pul-
monary inflammatory disease associated with intense airway
remodeling. As a consequence our efforts were focused on the
identification of potent and highly selective inhibitors of MMP-12.
We have recently disclosed the identification of orally effica-
cious MMP-12 inhibitors MMP408 and MMP145 for the potential
treatment of COPD and asthma.8,9 MMP408 in particular (com-
pound 1, Fig. 1) has shown good potency against hMMP-12
(IC50 = 2.0 nM), and excellent selectivity (>150- to ꢀ1000-fold)
over other MMPs. This compound also demonstrated oral efficacy
in an hMMP-12 induced lung inflammation mouse model with a
good dose response relationship.7
As aryl carbamate 1 moved forward in development, trace
amount of its toxic aniline metabolite 2 (Fig. 1) was identified
in vivo. It raised major concerns over the further progression of
candidate 1 down the development pathway. As a result, we set
out to make structural changes to our lead compounds that would
allow us to maintain the desirable pharmacologic profile of po-
tency and MMP-selectivity while reducing the risk of metabolic
degradation to provide aniline 2.
Several chemistry plans were proposed to address this meta-
bolic problem. The first strategy explored toward this goal involved
the synthesis of a series of compounds wherein the secondary aryl
carbamate was replaced with N-linked heterocycles. The general
synthetic route for this series commenced with nitration of diben-
zofuran 3 using fuming HNO3 in TFA, followed by hydrogenation in
⇑
Corresponding author.
E-mail address: charliewu09@yahoo.com (Y. Wu).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.046

Y. Wu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 138–143
139
O
O
H
N
O
HO
HO
NH2
NH
S
O
NH
S
O
O
O
O
O
O
1 (MMP-408)
hMMP-12 IC50 = 2 nM
Ames negative
2
Aniline metabolite
Ames positive
Figure 1. Metabolic pathway of compound 1.
HO
S
c
a, b
H2N
O
O
O
O
3
4
5
O
O
Br
Br
NH2
H
N
O
O
Cl
d, e
S
S
O
O
O
O
O
O
f
6
7
O
O
N
N
R
R
H
H
HO
O
N
N
R
NH2
h
S
S
g
O
O
O O
O
O
9
8
Scheme 1. Reagents and conditions: (a) HNO3 (fuming), TFA, rt, 2 h, 70%. (b) H2, Pd/C, MeOH, 100%. (c) (i) AcOH, HCl. NaNO2, (ii) CuCl2, AcOH, SO2, 0 °C to rt, 20 h, 60%. (d) Cl2,
AcOH/H2O, 0 °C to rt, 8 h, 80%. (e) Br2, AcOH, 76 °C, 6 h, 90%. (f) i-Pr2NEt, CH2Cl2, rt, 18 h, 95%. (g) Pd(DBA)2, P(O-tolyl)3, NaOBu, toluene, 105 °C, 18 h, 20–60%. (h) TFA, CH2Cl2,
rt, 6 h, 70–95%.
Table 1
IC50 SAR summary of N-linked dibenzofuran analogs
O
R
HO
NH
S
O
O
O
Entry
10
R
hMMP-12 IC50 (nM)
Selectivity (fold)
MMP-13/MMP-12
MMP-8/MMP-12
O
O
2.0
88
19
N
N
11
12
13
15
34
37
4
N
N
N
N
15
CF3
N
N
13
0.7
349
44
14
15
16
23
18
2.2
34
2
N
NH
N
38
0.5
3
N
N
154
O

140
Y. Wu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 138–143
O
O
Br
R
H
N
H
N
R
B(OH)2
a
O
O
S
S
O O
O O
O
O
7
17
O
R
H
HO
b
N
S
O O
O
18
Scheme 2. Reagents and conditions: (a) Pd(PPh3)4, K2CO3, dioxane, microwave, 120 °C, 15 min, 60–95%. (b) TFA, CH2Cl2, rt, 6 h, 70–95%.
Table 2
IC50 SAR summary of C-linker dibenzofuran analogs
R
O
HO
NH
S
O
O
O
Entry
19
R
hMMP-12 IC50 (nM)
Selectivity (fold)
MMP-13/MMP-12
MMP-8/MMP-12
0.4
900
33
O
20
21
22
0.1
0.1
0.2
3270
1440
1690
300
70
O
O
S
Cl
100
23
24
0.2
1200
125
S
NH
<1.0
>1130
>2500
N
25
0.4
525
143
N
H
N
26
27
1.0
1.2
1980
460
154
158
S
S
N
the presence of Pd/C to provide aniline 4 in quantitative yield
(Scheme 1). Conversion to sulfinic acid 5 from aniline 4 took placed
in two steps in 60% yield.10 Further oxidation to the sulfonyl chlo-
ride,11 and subsequent bromination provided aryl bromide 6. Treat-
The IC50 data of these N-heterocyclic analogs measured against
human MMP-12 are shown in Table 1. In general, these analogs are
potent MMP-12 inhibitors, with compound 13 reaching sub-nano-
molar potency. While moderate selectivity over MMP-13 was ob-
served (30- to 150-fold), the major shortcoming for this series of
analogs is the lack of MMP-8 selectivity, a major concern based
on the recent literature.13 In addition to the poor selectivity over
MMP-8, the pharmacokinetic (PK) data of N-linked heterocycle
ment with L-valine tert-butyl ester furnished the sulfonamide, and
subsequent Buchwald–Hartwig12 cross-coupling of aryl halide 7
followed by hydrolysis under acidic conditions provided the desired
target compounds 9.

Y. Wu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 138–143
141
atom. The sulfone oxygen interacts with the backbone through
hydrogen bonding. The specificity loops of MMPs have great simi-
larities in size and shape, with MMP-12 having relatively small and
predominantly hydrophobic pocket among those enzymes. By fine
tuning the structure of the cyclic hetero-atom ring in the deep S10
pocket, we were able to improve the potency and selectivity.
With the guidance of X-ray co-crystal structure and also based
on the previous modeling, our strategy was to design and incorpo-
rate a functional group to optimize the occupancy of the S10 pocket
and hence maximize the hydrophobic interactions to gain the
selectivity. It seems that small five-membered heterocyclic rings
fit well in the S10 pocket. One of our investigations was focused
on oxadiazole heterocyclic ring substitutes on the DBF scaffold.
The exemplary synthetic route is outlined below (Scheme 3).
The synthesis started with the intermediate 6, which reacts
Figure 2. X-ray co-structure of compound 26.
analogs (not shown here) were only moderate (bioavailability
range of 14%–27%), the poor bioavailability may be related to their
high clearances of those N-linked compounds. Although these ana-
logs reduce the risk of metabolic degradation to the corresponding
aniline, the team decided to further explore an alternative ap-
proach targeting C-linked analogs.
with L-valine methyl ester to form sulfonamide 28 in 92%. Cyana-
tion of the aryl bromide 28 with zinc cyanide catalyzed by
Pd(PPh3)4 under microwave irradiation afforded the cyanide 29
in good yield. The compound 29 was treated with hydroxyamine
in the presence of a base to produce the desired hydroxyamidine
Preparation of the C-linker analogs was straightforward and the
synthetic scheme is shown below (Scheme 2).
Table 3
SAR summary of oxadiazole analogs
Suzuki–Miyaura coupling of compound 7 (from Scheme 1)
with aryl bromides under microwave irradiation afforded a vari-
ety of C-linked compounds 17,14 which were treated with TFA
to convert the tert-butyl ester into the desired carboxylic acids
18 in high yields.
A variety of C-linked analogs have been synthesized and the IC50
values of selected compounds are summarized in Table 2 below.
Based on the data listed in Table 2, significant improvements on
potency against MMP-12 and selectivity over MMP-8 and MMP-13
have been achieved. For example, the potency of compounds 19–
25 reached the sub-nanomolar range. As for the selectivity over
MMP-13, it had been achieved greater than 1000-fold as indicated
by compounds 21, 22, 23 and 24. The most remarkable improve-
ment is the selectivity over MMP-8. For the first time in our lab,
selectivity over MMP-8 with more than a 100-fold is obtained
(compounds 20, 24, 26, and 27).
O
O
HO
N
R
N
NH
S
O
O
O
Entry
R
hMMP-12 IC50 (nM)
Selectivity (fold)
MMP-8/MMP-12
33
34
35
36
37
38
39
40
41
42
43
Me
Et
i-Pr
t-Bu
i-Bu
8.6
2.9
4.5
17
5.4
1.9
2.2
1.6
2.3
7.2
4.0
0.2
1.4
19
11
21
10
45
56
44
92
60
CH2OCH3
CF3
Cyclopropyl
Cyclobutyl
Cyclohexyl
Ph
In addition, we were able to obtain the X-ray co-crystal struc-
ture of compound 26 with MMP-12, which provides valuable infor-
mation for understanding its interaction with the enzyme. As
illustrated in Figure 2, the tricyclic dibenzofuran fully occupies
the S10 pocket, while the carboxylic acid coordinates with the zinc
O
44
0.3
100
O
O
NH2
Br
Br
H
O
O
N
b
Cl
S
S
a
O O
O O
O
O
6
28
H2N
O
O
CN
NOH
H
N
H
N
O
O
O
c
d
S
S
O O
O O
O
O
O
30
29
O
O
N
R
N
R
O
O
N
N
H
N
H
N
HO
e
S
S
O O
O O
O
31
32
Scheme 3. Reagents and conditions: (a) i-Pr2NEt, CH2Cl2, rt, 18 h, 92%. (b) CuCN, Pd(PPh3)4, NMP, microwave, 120 °C, 1 h, 80%. (c) NH2OH, TEA, rt, 6 h, 95%. (d) (i) RCOCl, DCM,
0 °C, 2 h, (ii) DMSO, 90 °C, 1 h, 75–88%. (e) LiOH, THF, water, 24 h, 60–95%.

142
Y. Wu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 138–143
16
14
12
10
8
R
Carbamate
Urea
Reverse Carbamate
C-Linker
O
HO
NH
S
O
O
O
6
Selectivity:
≥100 fold
4
2
0
0
100
200
400
500
600
MMP-13300IC50 (nM)
Figure 3. Comparison of N-linked compounds versus C-linked compounds.
30.15 Formation of the oxadiazole compound 31 from 30 was car-
ried out in DMSO at 90 °C. Saponification of 31 (LiOH in aqueous
THF) afforded the final product 32 in good yield.
Based on the above data and the physical properties, compound
26 was chosen as the lead for further in vitro profiling and PK studies
(Table 4 below). As shown, the crystalline form of compound 26 has
good aqueous solubility and exhibits negative results for the Ames
and hERG tests. It has excellent selectivity over other human MMPs,
which is a remarkable improvement over the N-linker series.8,9 For
example, the selectivity over MMP-13 for compound 26 has been
improved to about 2000-fold comparing with only 60-fold of
MMP408. Compound 26 was also profiled for cross-species MMP-
12 activities. As shown at the Table 4, this compound has nearly
equal potency for sheep MMP-12, while retaining a moderate po-
tency profile against the MMP-12 from other species. It also has im-
proved PK profile over the N-linker DBF analogs, especially the lower
clearance (5 mL/min/kg) and higher bioavailability (F = 63%).
Thus, compound 26 was further evaluated orally in two animal
models: the mouse ear-swelling model and the lung inflammation
model. To evaluate the compound in vivo initially, a MMP-12
dependent pulmonary inflammatory response was induced in
The IC50 values of the oxadiazole analogs are summarized in
Table 3 below. These analogs are very potent MMP-12 inhibitors
in general. It appears that there is a limited tolerance for the size
of the R group. The enzyme can tolerate a small aliphatic chain
(compounds 34, 37, 38) or rings (40, 41, and 42), but, not the bulky
t-butyl (36 vs 37) group. It is also notable that the oxygen-contain-
ing R groups give better potency (38 and 44). Selectivity over
MMP-8 is moderate with only compound 44 reaching 100-fold.
To compare the selectivity between the C-linker and the N-lin-
ker compounds, the IC50 values of MMP-12 were plotted against
those values for MMP-13 (Fig. 3 below). It is clear that the selectiv-
ity over MMP-13 for the C-linker analogs (blue rectangles) is great-
er than for both the carbamate (red rectangles) and the urea (black
rectangles) counterparts. It is probably due to the better hydropho-
bic interaction of C-linked compounds.
Table 4
Selectivity and PK profile of compound 26
O
HO
N
S
NH
S
O
O
O
Compound 26
M.W.: 430
Solubility:
Ames Test:
hERG Test:
0.55mg/ml (pH=7.4)
Negative
tPSA: 129
Negative
cLogP: 4.31
Selectivity profile (IC50 in nM)
MMP-12
1.0
MMP-2
501
MMP-3
2530
MMP-7
57,700
MMP-8
154
MMP-9
1970
MMP-13
1980
MMP-12 activities over species (IC50 in nM)
Human
1.0
Mouse
Rabbit
57
Dog
70
Monkey
244
Sheep
5.4
85
PK properties
Dose PO (mg/kg)
10
Dose iv (mg/kg)
2
Vdss (L/kg)
0.8
CL (mL/min/kg)
5
T1/2 (h)
2.9
Cmax (ng/mL)
5550
AUC (h ng/mL)
20,317
F %
63

Y. Wu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 138–143
143
120.0
100.0
80.0
60.0
40.0
20.0
0.0
compound 26 to reduce the response. The time course for the
rhMMP-12 induced lung inflammation being affected was over a
24–72 h time period, rather than a more acute 2 h time period
evaluated in the ear-swelling. In addition to induction of endoge-
nous mouse MMP-12, other induced mediators are likely affecting
the resulting inflammatory response as well. In other studies we
demonstrated that the no effect dose for compound 26 in the lung
inflammation model was 3-mg/kg PO, BID in contrast to the ear-
swelling model where an effect was seen with this dose. We be-
lieve there was a good correlation with efficacy and exposure with
the compound in this model.
In summary, we have successfully identified a series of potent
and selective MMP-12 inhibitors, which have the DBF core with a
variety of C-linked heterocyclic rings as attachments. These new
analogs exhibit improved MMP-12 potency and selectivity against
other human MMPs over the N-linker analogs reported previously.
Among these new analogs, compound 26 was selective for further
in vitro and in vivo profiling. In addition to an overall improve-
ment, this compound showed good oral efficacy in both the mouse
ear-swelling model and lung inflammation model at the desired
dose regimen. Compound 26 was further advanced to the Develop-
ment Track status.
Vehicle treated
3mg/kg
10mg/kg
P<.001
24.9%
30mg/kg
P<.001
38.63%
P<.001
65.22%
2hr
Time post challenge
Figure 4. Effect on rhMMP-12-induced mouse ear swelling model (3, 10 and
30 mg/kg, PO, BID) of compound 26.
Total BAL
1.5×1006
p<0.015
p<0.007
IN Vehicle
1.0×1006
MMP-12+IN 10mg/Kg
Acknowledgments
MMP-12+IN 5mg/Kg
MMP-12+IN MC/T
5.0×1005
The authors are grateful to Dr. Nelson Huang and Ms. Ning Pan
for LC-MS measurements, Drs. Walter Massefski and Vasilios
Marathias for the contribution of NMR analysis, Drs. John Kubera
and Franklin Schlerman for the lung inflammation experiments
and Drs. Iain McFadyen and Diane Joseph-McCarthy for molecular
modeling help.
0.0×1000
Figure 5. Effect on rhMMP-12 induced lung inflammation (5 and 10 mg/kg, PO
(BID)) of compound 26.
References and notes
C57BL/6 mice by a single intradermal injection of recombinant hu-
man MMP-12 (rhMMP-12) in the ear. Compound 26 was adminis-
tered orally (PO, BID) 12 h and 2 h prior to rhMMP-12 challenge.
Swelling was measured as an increase in ear thickness 2 h post
rhMMP-12 challenge. To evaluate the compound in the lung, an
MMP-12 dependent pulmonary response was induced in C57BL/6
mice by intranasal administration of rhMMP-12 for three consecu-
tive days. Compound 26 was administered (PO, BID) 2 h prior to,
and 12 h after each of the three rhMMP-12 challenges. Lung
inflammation was assessed 24 h after the final rhMMP-12 chal-
lenge. The detailed procedures for the in vivo pharmacology tests
have been described previously.8,9
The mouse ear-swelling model is shown in Figure 4 below.
Compound 26 has showed significant reduction in ear-swelling
model at all the three doses tested (3, 10, and 30 mg/kg, p
<0.001) when comparing to the vehicle control. The results of
mouse ear-swelling model of compound 26 are comparable with
that of compound MMP408.
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Figure 5 below illustrates the efficacy of compound 26 against
the rhMMP-12 induced mouse lung inflammation model. It
showed significant reduction in total BAL inflammation (>50% inhi-
bition, p <0.007) compared to the control (the black bar—MMP-12
with the vehicle). Further study demonstrated that the minimum
efficacious dose for compound 26 was 5 mg/kg (PO, BID) in this
lung inflammation model.
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In general, the lung inflammation model may be more stringent
than the ear-swelling model in that it required a higher dose of