Macrocyclic amino carboxylates as selective MMP-8 inhibitors.

Full text of DOI:10.1021/jm970850y

J . Med. Chem. 1998, 41, 1749-1751
1749
Ma cr ocyclic Am in o Ca r boxyla tes a s
Selective MMP -8 In h ibitor s
Robert J . Cherney,* Li Wang, Dayton T. Meyer,
Chu-Baio Xue, Zelda R. Wasserman,
Karl D. Hardman, Patty K. Welch,†
Maryanne B. Covington,† Robert A. Copeland,
Elizabeth C. Arner,† William F. DeGrado,1 and
Carl P. Decicco
Chemical and Physical Sciences and Inflammatory Diseases
Research, The DuPont Merck Pharmaceutical Co.,
Experimental Station, Wilmington Delaware 19880-0500
Received December 19, 1997
Matrix metalloproteinases (MMPs) are a family of
zinc-containing endopeptidases needed for normal turn-
over and maintenance of the extracellular matrix.2
Their proteolytic activity is tightly controlled by endog-
enous tissue inhibitors of metalloproteinases (TIMPs)
and the nonspecific R2-macroglobulins.3 Disruption of
this balance and overproduction of the MMPs results
in the degradation of the matrix, which includes carti-
lage and connective tissues. As a result, the MMPs have
been implicated in several diseases including arthritis4
and tumor metastasis.5 Inhibition of the MMPs, there-
fore, has gained considerable attention and has become
an important strategy in the development of novel
therapeutics. However, with the large number of MMPs
now characterized, the selective inhibition of the thera-
peutically relevant MMP(s) will be of paramount im-
portance when considering the potential toxicity of a
chronically dosed drug acting on enzymes involved in
tissue turnover. We have been interested in, and have
recently disclosed, the synthesis of potent carboxylates
as broad6 and selective7 inhibitors of the MMPs. In an
effort to improve potency, selectivity, and metabolic
stability of these linear inhibitors, we investigated
macrocyclic amino carboxylates linked from P1 to P2′,
having the general formula 1. In this communication,
we describe the discovery of a novel class of macrocycles
as selective MMP-8 inhibitors.
F igu r e 1. Carboxylate 2 was cocrystallized in MMP-3.6 The
figure shows the structure of carboxylate 2 extracted from the
X-ray crystal structure (carbons are yellow with nitrogen blue
and oxygen red).
ing toward solvent, away from the active site, where
they become situated in close proximity to each other.
This is a similar observation to that made in the pre-
vious paper for succinate hydroxamates.9 Thus, we
surmised the P1 and P2′ groups of an amino carboxylate
could be connected to form a macrocycle of varying size.
The solvent exposed area is large, and therefore we felt
confident that the macrocycle, and various linking
groups, would be accommodated there. Amino carboxy-
lates orient themselves differently than the hydroxam-
ates described in the previous paper,9 and this was
taken into account in our modeling. This difference is
manifested through the extra atom (nitrogen) in the
extended conformation and a distinct mode of ligation
to the active site zinc. From modeling, the larger ring
amino carboxylates appeared to better preserve the
extended conformation and the projection of the car-
boxylate to the active site zinc. To model this, the 14-
membered lactam 12 was docked into the active site of
MMP-3. This orientation was refined with 20-ps of
molecular dynamics using the procedure of Luty et al.10
Figure 2 shows the average structure during the final
3-ps of the run, which was overlapped with the crystal
structure of carboxylate 2. This demonstrates that the
macrocycle is a good mimic of the overall gross structure
and provides for excellent overlap of the carboxylate
moieties. Simulations were also carried out on lactam
12 within the active site of MMP-8.11 The 3-ps average
structure from the end of the run is displayed in Figure
3. This representation indicates that the lactam 12 is
capable of participating in the typical hydrogen bond
network well documented12 for MMP inhibitors.
Sch em e 1
Design . In a recent report,6 we disclosed the X-ray
crystal structure of carboxylate 2 cocrystallized with
MMP-3.8 As shown in Figure 1, carboxylate 2 has its
P1 (n-butyl) and P2′ (p-methoxybenzyl) residues extend-
Syn th esis. The macrocyclic amino carboxylates were
synthesized by the representative route shown in Scheme
† Inflammatory Diseases Research.
S0022-2623(97)00850-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/01/1998

1750 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Communications to the Editor
Ta ble 1.
Ki (nM)a
compd
n
W
R
MMP-1
MMP-2
MMP-3
MMP-8
MMP-9
13
11
12
14
15
linear
2860
900
2500
8400
1448
1533
2400
8100
238
14088
35000
13500
2900
293
531
17
10
9
404
9800
6600
5800
288
1
2
2
2
-CH2-
Ph
Ph
Ph
PhPh
-CH2-
-O2CCH2-
-CH2-
249
2400
a
Ki’s were determined as previously described.9,16
F igu r e 3. The minimized10 14-membered lactam 12 (carbons
are gray with nitrogen blue and oxygen red) docked into
MMP-8 (carbons are white with nitrogen blue and oxygen red;
catalytic zinc is orange).
F igu r e 2. Overlay between the minimized10 14-membered
lactam 12 (carbons are white with nitrogen blue and oxygen
red) and carboxylate 2 from Figure 1 (carbons are yellow with
nitrogen blue and oxygen red).
toward MMP-8 was observed for 12 when compared to
the 13-membered lactam 11. In addition, the selectivity
of 12 for MMP-8 was enhanced as compared to the other
MMPs we screened. In keeping with this trend, we
synthesized the 16-membered lactam 14. Again, an
increase in activity toward MMP-8 was observed for 14
versus the 14-membered lactam 12. However, 14 was
more potent against MMP-2, -3, and -9, and therefore
less attractive than the selective 12.
2 for carboxylate 11. The aspartic acid derivative 3 was
coupled to lysine 4 via a standard EDC coupling. The
resulting amide 5 was treated with diethylamine to
remove the Fmoc group and provide the primary amine
6. In general, we found that amines of this type could
be efficiently alkylated13 with triflate 714 to afford, in
this case, the secondary amine 8. Catalytic hydrogena-
tion gave the amino acid 9, which was cyclized under
moderate dilution to yield the 13-membered lactam 10.
All that remained to complete the synthesis was re-
moval of the tert-butyl group via TFA, thus providing
the target macrocyclic amino carboxylate 11.
Resu lts a n d Discu ssion . The smallest macrocycle
synthesized was the 13-membered lactam 11, which
displayed less affinity for MMP-2, -3, -8, and -9 when
compared to the model, linear compound 13 (Table 1).
As discussed above, the larger rings appeared superior
from modeling, and therefore we synthesized the 14-
membered lactam 12. A 30-fold increase in activity
Another way to gain affinity in this class of inhibitors
is to install biaryl groups in P1′.6,15 The resulting biaryl
lactam 15 was only slightly more active toward MMP-8
than the parent 12. The main limitation of the biaryl,
however, is the enhanced affinity toward other MMPs
with large S1′ pockets. In fact, this was observed for
15, as the inhibition of MMP-2, -3, and -9 increased
dramatically. It is interesting to note that the biaryl
had only a modest effect on MMP-1, known to have a
restricted S1′.

Communications to the Editor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1751
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a
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potent MMP-8 inhibitors. With the proper ring size and
substituents, potent and selective MMP-8 inhibitors
have been described. These unique structures should
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MMPs, as well as aid in the development of future
inhibitors.
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J M970850Y