A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): Discovery of (S)- 2-(8-(Methoxycarbonylamino)dibenzo[b,d]furan- 3-sulfonamido)-3-methylbutanoic acid (MMP408)

Article abstract of DOI:10.1021/jm900093d

Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead optimization and has good physical properties and bioavailability. The compound blocks rhMMP-12-induced lung inflammation in a mouse model and was advanced for further development for the treatment of COPD.

Full text of DOI:10.1021/jm900093d

J. Med. Chem. 2009, 52, 1799–1802
1799
A Selective Matrix Metalloprotease 12 Inhibitor
for Potential Treatment of Chronic Obstructive
Pulmonary Disease (COPD): Discovery of (S)-
2-(8-(Methoxycarbonylamino)dibenzo[b,d]furan-
3-sulfonamido)-3-methylbutanoic acid
(MMP408)
Wei Li,*,† Jianchang Li,† Yuchuan Wu,† Junjun Wu,†
Rajeev Hotchandani,† Kristina Cunningham,†
Iain McFadyen,† Joel Bard,† Paul Morgan,‡
Franklin Schlerman,‡ Xin Xu,§ Steve Tam,†
Samuel J. Goldman,‡ Cara Williams,‡ Joseph Sypek,‡ and
Tarek S. Mansour†
Figure 1. Two approaches for modification of the lead compound 1.
Chemical Sciences, Inflammation, and Drug Safety and Metabolism,
Wyeth Research, 200 Cambridge Park DriVe,
Cambridge, Massachusetts 02140
ReceiVed January 22, 2009
Abstract: Matrix metalloprotease 12 plays a significant role in airway
inflammation and remodeling. Increased expression and production of
MMP-12 have been found in the lung of human COPD patients.
MMP408 (14), a potent and selective MMP-12 inhibitor, was derived
from a potent matrix metalloprotease 2 and 13 inhibitor via lead
optimization and has good physical properties and bioavailability. The
compound blocks rhMMP-12-induced lung inflammation in a mouse
model and was advanced for further development for the treatment of
COPD.
Figure 2. Homology model indicates similar loops in shape and size
for MMP-12 (green in color) and -13 (purple), which poses great
challenges for selectivity.
Chronic obstructive pulmonary disease (COPDa) is a chronic
progressive respiratory disease characterized by airflow limita-
tion that is not fully reversible.1 COPD is associated with an
abnormal inflammatory response of the lung to noxious particles
or gas, mainly caused by cigarette smoke. The disease ranks
among the top five leading causes of death and is expected to
grow because of increased prevalence with increasing age,
cigarette smoking, and environmental factors.2 Presently, there
are only symptomatic therapies,3 and no disease-modifying
drugs are available for this indication.4,5 Pathologic degradation
of the extracellular matrix (ECM) of the bronchial wall may
represent an important cause of airflow obstruction in COPD.
Matrix metalloproteases (MMPs) have been suggested to be the
major proteolytic enzymes to induce this progressive airway
remodeling.6
12-deficient mice show significantly impaired macrophage and
neutrophil recruitment in response to cigarette smoke8,9 and
markedly reduced TNF-R production.10 Pathological evidence
indicates that MMP-12-deficient mice are protected against the
development of emphysema induced by cigarette smoke.8
Establishing high quality leads with attractive physical
properties was the target at the inception of the program. In
addition to mining hits generated from the HTS, activity and
selectivity data generated by all of our in-house MMP programs
were available to us. One structure in particular that drew our
attention was 1, a lead from the MMP-13 program (Figure 1).11
Compound 1 (Figure 1) is a potent MMP-2/-13 inhibitor with
excellent MMP-12 activity (IC50 ) 14 nM). As illustrated by
the model shown in Figure 2, the carboxylic acid acts as a zinc-
chelating group (ZCG) and the biphenyl rings sit in the S1′
pocket. The benzofuran attachment is located deep in the S1′
pocket close to the solvent front.
MMP-12, in particular, has been shown to play a significant
role in airway inflammation and remodeling. MMP-12 is the
primary elastolytic enzyme of alveolar macrophages.7 Preclinical
studies in COPD/emphysema support blocking MMP-12 as a
valid approach for therapeutic intervention. Specifically, MMP-
On the basis of the model, the specificity loops12 of MMP-
12, -13, and -2 (not shown) have great similarities in size and
shape, with MMP-12 having the smallest among the three
enzymes. For the MMP-13 program, the selectivity over MMP-2
and -12 was successfully achieved by increasing the number
and size of the substituents at the C3 and C5 positions of the
benzofuran so that they clash with the smaller loops of MMP-
12 and -2 but not MMP-13.13,14 Extending in that direction
(approach A, Figure 1) would be not viable for the MMP-12
program, since the MMP-12 loop would be hit first before
reaching to the loops of MMP-2 and -13.
* To whom correspondence should be addressed. Phone: 1-617-665-5625.
Fax: 1-617-499-1017. E-mail: weili@wyeth.com.
†
Chemical Sciences.
Inflammation.
Drug Safety and Metabolism.
‡
§
a Abbreviations: MMP-12, matrix metalloprotease 12; ECM, extracellular
matrix; MMP-13, matrix metalloprotease 13; MMP-2, matrix metallopro-
tease 2; COPD, chronic obstructive pulmonary disease; HTS, high-
throughput screening; ZCG, zinc-chelating group; DBF, dibenzofuran; SAR,
structure-activity relationship; PK, pharmacokinetics; HLM, human liver
microsomes; MLM, mouse liver microsomes; hERG, human ether-a-go-go
related gene; q.d., quaque die; b.i.d., bis in die; po, per os.
On the other hand, approach B, which goes in the direction
orthogonal to approach A, appeared to be very attractive.
10.1021/jm900093d CCC: $40.75
2009 American Chemical Society
Published on Web 03/11/2009

1800 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Table 1. Selectivity Achieved with DBF Analogues
Letters
Table 2. SAR of Sulfonamide, Carbamate, and Urea Analogues
IC50 (nM)
IC50 (nM)
MMP- MMP-
compd 12 13
compd
MMP-12
MMP-13
selectivity, MMP-12/-13
substituents
A/C ring
R
X
Y
1
14
38
600
1.3
2500
0.1
65
42
(R)-2a
(S)-2b
C2
C2
C2
C2
C2
C3
C3
C2
C2
C2
C2
C2
C2
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C7 methyl
C7 methyl
C7 isopropyl
C7 4-(3,5-dimethyl)isoxazole
C7 phenyl
C8 methyl
C8 2,2,2-trifluoroethyl
C7 O-methyl
C7 O-n-propyl
C7 O-isopropyl
C7 O-phenyl
SO2 (R)-3a 11.0 1100
SO2 (S)-3b 170.0 25000
25000
SO2 (R)-4
SO2 (R)-5
SO2 (R)-6
SO2 (S)-7
SO2 (S)-8
CO (R)-9
50.0 120
2500 34000
Molecular modeling indicated that there is a 30° dihedral angle
between the two phenyl rings in 1. The design of new scaffolds
that change this dihedral angle or restrict the rotation of the
biphenyl rings would be a novel approach. This could be
accomplished by linking the biphenyl rings with a heteroatom
to form a tricyclic core, effectively realizing the expansion at
the S1′ pocket.
To our delight, the new molecules synthesized on the basis
of a dibenzofuran (DBF) scaffold15 achieved impressive selec-
tivity over MMP-13 while maintaining decent MMP-12 activity
(Table 1). By comparison to 1, which favors MMP-13 over
MMP-12, the new analogues showed better potency toward
MMP-12 than MMP-13, a complete reversal of selectivity.
Compound 2a represents a true breakthrough in selectivity over
MMP-13 with a remarkable 650-fold increase compared to 1.
An aspect of chiral recognition is also observed. Similar to
the trend in selectivity, the (R)-isomer exhibits better potency
than the (S)-isomer. Although the MMP-12 potency of these
analogues is weaker than that of 1, further improvements could
be achieved through chemical modification.
100
6000
10.3 93
70.0 670
7.2
500
CO (R)-10 14.0 109
CO (R)-11 39.0 500
CO (R)-12 45.0 600
C7 O-methyl
C7 O-methyl
C8 O-methyl
C8 O-ethyl
8-Br CO (R)-13a 1050 25446
8-Br CO (S)-13b 3900 >25000
CO (S)-14
CO (S)-15
CO (S)-16
CO (S)-17
CO (S)-18
CO (S)-19
CO (S)-20
CO (S)-21
CO (S)-22
CO (S)-23
CO (S)-24
CO (S)-25
CO (S)-26
CO (S)-27
CO (S)-28
CO (S)-29
2.0
5.0
5.6
4.7
2.1
10.2 220
6.6
8.1
120
100
10
10
10
C8 O-n-propyl
C8 O-isobutyl
C8 O-(2-fluoro)ethyl
C8 O-phenyl
C8 O-(2-Cl)phenyl
C8 O-(4-F)phenyl
C8 O-(4-Me)phenyl
C8 NH2
C8 N-cyclopentyl
C8 N-thiophen-3-yl
C8 N-(thiophen-2-yl)ethyl
C7 O-methyl
180
200
14.0 100
7.6
5.0
0.9
1.1
59.0
2.1
3.3
1.1
12.0 >1000
10.0 97
16.0 361
C7 O-(2-fluoro)ethyl
C7 O-(4-fluoro)phenyl
The X-ray cocrystal structure with the MMP-12 enzyme
provided useful information for understanding the inhibitor-
enzyme interaction and reliable information for modeling. For
example, modeling suggested there was no space for substitution
at the C1, C4, C6, and C9 positions along the spherical tricyclic
core, which guided the efforts in SAR development to focus
on the remaining positions C2, C3, C7, and C8. There are only
four possible combinations of regioisomers given a set of
substituents, namely, C2/C7, C2/C8, C3/C7, and C3/C8. The
C2/C8 combination was ruled out as less favorable on the basis
of modeling. The SAR development was thus focused on the
remaining three combinations (Table 2).
combination (14-22) are more potent than those of C2/C7
(9-13). For example, the IC50 of the C3/C8 isomer 14 is 2 nM,
whereas the C2/C7 regioisomer methyl carbamate 9 is 7.2
nM. Similar results are observed for 10 and 16 (14.0 vs 5.6
nM, respectively). There is no tolerance toward ortho-substitu-
tion to the carbamate moiety, as an 8-Br substituent (13a and
13b) dramatically reduced the potency compared to 9. As to
the potency of the C3/C7 regioisomers, they are also less potent
in general than their C3/C8 counterparts. For example, the
2-fluoroethyl carbamate 18 (C3/C8) has an IC50 value of 2.1
nM, whereas the C3/C7 isomer 28 experienced a 5-fold drop
in potency to 10 nM.
Table 2 shows the results of SAR studies of the sulfonamide,
carbamate, and urea analogues derived from the C-ring modi-
fication. As shown by the IC50 values (average of multiple tests),
potencies of some analogues increased to single digit nanomolar.
For the sulfonamide derivatives, their potencies against MMP-
12 spread from 10 nM to 2.5 µM favoring smaller alkyl groups
on the sulfonamide. For example, potency was gained by 3.5-
fold for 3a compared to 2a with an unsubstituted C-ring. The
improved potency over the unsubstituted analogues indicates a
favorable interaction of the sulfonamide moiety with the protein
backbone in the deeper S1′ pocket. Similar chiral recognition
is also observed. For example, the IC50 of enantiomer (R)-3a is
16-fold more potent than (S)-3b, with the (R)-enantiomer being
the favored configuration. Selectivity over MMP-13 was
maintained. The best selectivity over MMP-13 among these
sulfonamides is demonstrated by 3a (100-fold) and 3b (147-
fold). It appears that there is little tolerance in regard to the
size of the R group for these sulfonamide analogues, as the
potency diminished dramatically with bigger R groups (5).
The SAR of the carbamate analogues is also well defined.
Unlike the sulfonamides, the regioisomers with the C3/C8
However, the urea derivatives have activities different from
those of the carbamates. The urea analogues (23-26) are very
potent MMP-12 inhibitors but less selective over MMP-13. In
fact, ureas 24-26 are nearly equipotent for MMP-12 and MMP-
13, implicating similar interactions of the urea residues with
the enzymes within the S1′ pocket of MMP-12 and MMP-13.
There is also more tolerance toward bigger substituents on the
urea nitrogen as shown by 25 and 26.
It is interesting to note that among the three methyl carbamate
regioisomers 9 (C2/C7), 14 (C3/C8), and 27 (C3/C7), 14 is the
most potent (2 nM) with 9 and 27 being equally potent (12.0
nM).
Efficient, interrelated routes for preparation of the three key
nitro-DBF sulfonyl chlorides 32, 34, and 36 were developed
according to their defined regiocombinations (eqs 1-3, Scheme
1). For example, sulfonyl chloride 32 (C2/C7 combination) was
prepared in two steps: nitration of DBF (30) generated the
desired 3-nitrodibenzofuran (31) in 70% yield,16 which was
treated with chlorosulfonic acid to generate 32 (Scheme 1,
reaction 1).

Letters
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1801
Table 3. Pharmacokinetic Data for Selected Compounds
compd
iv (mg/kg)
Vdss (L/kg)
CL ((mL/min)/kg)
po (mg/kg)
T1/2 (h)
Cmax (ng/mL)
AUC (hang/mL)
F (%)
3a
9
14
15
26
2
2
2
2
2
1.9
1.6
1.9
1.6
15.6
141.3
8.3
17.2
19.0
211.0
30
30
30
30
10
2.0
2.7
3.0
3.4
NAa
103
245
7
36
27
42
10583
3084
7791
NAa
21659
7476
10834
NAa
a Systemic exposure was negligible.
Scheme 1. Preparation of the Key DBF Intermediatesa
Scheme 2. Preparation of Compound 14a
a Reagents and conditions: (a) HNO3, TFA (70-95%); (b) (i) HSO3Cl
in CHCl3, 85%; (ii) SOCl2, DMF (cat.) 90%; (c) (i) Pd/C, H2, CH3OH; (ii)
NaNO2, HCl; (iii) SO2, CuCl, 74%; (d) Br2, HOAc, 70 °C, 4 h, 80%.
a Reagents and conditions: (a) (L)-valine esters, TEA, in DCM, 94%;
(b) Pd/C, H2, MeOH, 98%; (c) methyl chloroformate, pyridine in DCM,
85%; (d) TFA/DCM, 98%.
Preparation of the nitrosulfonyl chloride 34 required manipu-
lations to generate the desired C3/C8 combination. The C3-
sulfonyl chloride 33 was made through reduction of the -NO2
in 31 to -NH2, which was further transformed to the diazonium
salt, followed by SO2 treatment in the presence of CuCl.17 The
desired sulfonyl chloride 33 was treated with HNO3 in TFA to
afford the desired nitroarene 34 in very good yield (conditions
c and a, Scheme 1). The different regiochemistry of the nitrations
on 30 and 33 may be attributed to the influence of the electron-
withdrawing sulfonyl chloride group in 33, which directs the
nitration to C8, furnishing 34.
Table 4. Cross-Species Activity and Selectivity Profile of 14
MMP-12 IC50 (nM) of Different Species
human
2.0
mouse
160
rat
sheep
22.3
320
IC50 (nM) of Other Human MMPs
-7 -9 -12 -13 -14 TACE Agg-1 Agg-2
120 1100 >25 µM >5 µM >10 µM
MMP-1 -3
>6 µM 351 >22 µM 1300
2
Compound 14 was also profiled for cross-species MMP-12
activity and selectivity against other human MMPs (Table 4).
Compared with human MMP-12, 14 has lower potency in rodent
MMP-12 (80- and 160-fold less active for mouse and rat,
respectively). This compound also maintains a good selectivity
profile over other human MMPs.
Preparation of the 8-bromo-7-nitrodibenzo[b,d]furan-3-sul-
fonyl chloride (36) required extensive manipulation to place the
nitro group at the desired C7 position. Bromination is a
necessary step to block the C8 carbon to generate 35 for the
subsequent regioselective C7 nitration to obtain 36. Removal
of the bromo and reduction of -NO2 to -NH2 could be
accomplished simultaneously via catalytic hydrogenation at a
later stage (conditions d and a, Scheme 1).
As illustrated in Scheme 1, preparation of the three key
intermediates is an integral chemistry effort for maximizing
synthetic efficiency. Thus, the synthetic approaches to the less
accessible and more complicated sulfonyl chlorides were
designed to commence from the penultimates of the simpler
ones (31 for 34, 33 for 36). General procedures to progress from
the sulfonyl chlorides to the final compounds are exemplified
in Scheme 2.
In the metabolic stability studies carried out in the liver
microsomal system, 14 appeared to be very stable in mouse,
rat, dog, monkey, and human (in vitro t1/2 > 60 min). An
acylglucuronide was the only metabolite detected in all species
at a very low level. Further in vitro metabolic stability of 14
was also determined in cryopreserved hepatocytes of dog,
monkey, and human. In this system, metabolism of 14 was low
to moderate in dog and very low in monkey and human. An
aniline metabolite was detected in this hepatocyte study, which
appears to be derived from the chemical degradation of the
methyl carbamate moiety.
Pharmacokinetic data (in C57BL/6 mice) indicate that car-
bamate analogues 9, 14, and 15 show better exposure and
bioavailability than the sulfonamide 3a and urea 26 (Table 3).
Compound 3a and 26 have high clearance rates (141.3 and 211.0
(mL/min)/kg, respectively) with low (3a) to very poor exposure
(26). Compounds 3a, 9, and 14 were tested in a mouse lung
inflammation model18 (30 mg/kg, po), and compound 14, (S)-
2-(8-(methoxycarbonylamino)dibenzo[b,d] furan-3-sulfonamido)-
3-methylbutanoic acid, showed the optimum in vivo efficacy
and thus was advanced as MMP408 for further preclinical
evaluation.19
Further drug safety evaluations for 14 were performed with
favorable results. For example, 14 exhibited a negative Ames
test and has no hERG activity.
Scheme 2 illustrates the synthesis of 14. The amino acid
moiety of 14 was installed via coupling of the sulfonyl chloride
34 with (L)-valine tert-butyl ester in the presence of base to
obtain 37. The nitro group on the C ring of 37 was reduced to
the corresponding aniline 38 in high yield via palladium
catalyzed hydrogenolysis. Compound 38 was then derivatized

1802 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Letters
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Figure 3. Oral efficacy of 14 in rhMMP-12 induced lung inflammation
(5 mg/kg, b.i.d. po vs MMP-12 plus vehicle).
by treatment with methyl chloroformate in the presence of a
mild base to generate the penultimate tert-butyl ester 39 in 85%
yield.
The tert-butyl ester 39 was hydrolyzed under acidic conditions
to generate the desired final product 14 with 73% overall yield
from 34. Originally, the (L)-valine methyl ester was used for
the preparation of 14. However, saponification of the corre-
sponding methyl ester penultimate under basic conditions
resulted in 14 but with contamination from the decomposition
of the carbamate moiety. Thus, it was replaced with the tert-
butyl ester. Chiral analysis of 14 confirmed that there was no
impurity from epimerization of the chiral center during the
synthesis.
To evaluate the compounds in vivo, an MMP-12 dependent
pulmonary inflammatory response was induced in C57BL/6
mice by intranasal administration of recombinant human (rh)
MMP-1218 for 3 consecutive days. Inflammation within the
bronchoalveolar lavage fluid was then quantified 24 h after the
final dose of rhMMP-12. Compound 14 showed significant
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0.001) and absolute macrophages (>70% inhibition, P < 0.001)
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at 30 mg/kg (po, q.d.) 2 h prior to each of the 3 doses of
rhMMP-12. Further studies determined that the minimum
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(Figure 3).
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scaffold, which also offers metabolic stability and good PK
properties. Compound 14, a potent, selective, and orally
available MMP-12 inhibitor was identified. The demonstrated
ability to attenuate pulmonary inflammation supports the
therapeutic potential of this compound for the treatment of
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Acknowledgment. The authors thank Thiru Singanallore and
Jean Schmid for synthetic support; Nelson Huang, Walter
Massefski, and Ning Pan for analytical support; Susan Fish,
Andrea Bree, and Mark Collins for supporting pharmacology
studies.
Supporting Information Available: Details of syntheses and
assays and characterization of all compounds. This material is
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