Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13

Article abstract of DOI:10.1016/j.bmcl.2007.09.085

Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitiors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to e

Full text of DOI:10.1016/j.bmcl.2007.09.085

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6529–6534
Potent, selective spiropyrrolidine pyrimidinetrione
inhibitors of MMP-13
Kevin D. Freeman-Cook,a,* Lawrence A. Reiter,a Mark C. Noe,a Amy S. Antipas,a
Dennis E. Danley,a Kaushik Datta,b James T. Downs,a Shane Eisenbeis,a James D. Eskra,a
David J. Garmene,a Elaine M. Greer,a Richard J. Griffiths,a Roberto Guzman,b
Joel R. Hardink,a Fouad Janat,a Christopher S. Jones,a Gary J. Martinelli,a
Peter G. Mitchell,a Ellen R. Laird,a Jennifer L. Liras,a Lori L. Lopresti-Morrow,a
Jayvardhan Pandit,a Usa D. Reilly,a Donald Robertson,b Marcie L. Vaughn-Bowser,a
Lilli A. Wolf-Gouvieaa and Sue A. Yocuma
aPfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA
bPfizer Global Research & Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
Received 20 July 2007; revised 24 September 2007; accepted 25 September 2007
Available online 29 September 2007
Abstract—Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused com-
pounds that are potent and selective inhibitiors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably
due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than
100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl–heteroaryl P10group.
When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite
the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
ꢀ 2007 Elsevier Ltd. All rights reserved.
In an effort to identify new compounds that can modu-
late the progression of osteoarthritis (OA), our group
has focused on inhibitors of MMP-13.1–11 In many re-
spects, MMP-13 appears to be an ideal point of thera-
peutic intervention in this debilitating disease. Not
only is MMP-13 present in human OA cartilage,12 and
co-localized with cleaved type II collagen,13 but it also
degrades both type II collagen and cartilage.14,15 An
agent that could slow or stop this process has been the
ultimate goal of many research groups over the last
two decades.16–25
finding has been the observation of musculoskeletal syn-
drome (MSS).6,26,27 This side effect is observed as signif-
icant joint stiffening, which is reversible when dosing is
interrupted. It is reasonable to suggest that this effect
is due to the inhibition of normal extracellular matrix
turnover, possibly due to inhibition of MMPs other
than MMP-13. To test this hypothesis, we began a
research program that was distinct from our earlier
efforts in this disease area,6 one designed to discover
potent MMP-13 inhibitors at least 100· selective against
a panel of related MMPs.1
Although a number of MMP inhibitors have been
advanced into clinical trials, the results of these studies
have been disappointing. The most consistent clinical
Recent publications by several groups, including ours,
have described the utility of the pyrimidinetrione as a
zinc binding moiety.1,2,20,21 As described by Reiter
et al., extension of a long, lipophilic P10substituent in
conjunction with the proper placement of heteroatoms
can produce compounds which meet our selectivity cri-
teria for development candidates. In a parallel effort, a
series of related spirocyclic analogs were also investi-
gated (Fig. 1).28
Keywords: Pyrimidinetrione; Matrix metalloprotease; MMP-13; Col-
lagenase-3.
*
Corresponding author. Tel./fax: +1 860 715 2658; e-mail: Kevin.
Freeman-cook@pfizer.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.09.085

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K. D. Freeman-Cook et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6529–6534
Figure 1. Sequential acyclic nitrogen replacement analogs, and proposed cyclization strategy.
A cyclic design would not be possible with a divalent
oxygen atom as a point of attachment, and would re-
quire a nitrogen atom link to the pyrimidinetrione.
Thus, our first objective was to explore sequential, single
atom changes to understand their separate effects on
potency and selectivity.
ated and unsubstituted cyclic ureas (8 and 9) were five-
fold less potent.
Since compounds 5 and 6 were less stable in solution
than the original lactam, we considered the possibility
that the solution instability was due to pyrimidinetrione
ring opening which would be enhanced by the presence
of electron withdrawing groups (e.g., lactam, sulfon-
amide). To test this idea, spirocyclic pyrrolidines were
prepared as shown in Scheme 1. Reaction of aminopyri-
dines with bromodiethylmalonate produced alkylated
aniline derivatives. These could be cyclized to pyrrolidines
by treatment with 1,3-dibromopropane and cesium car-
bonate in DMF. The 2,20-dicarboxyethyl pyrrolidines
could then be converted to the corresponding pyrimidin-
etrione by treatment with urea and sodium ethoxide.
The single change of nitrogen for carbon at position X, 1
versus 2 (Table 1), showed a distinct drop in potency,
and reduced MMP-12 selectivity relative to compound
1.29 The threefold improvement in potency of diaza ana-
log 3 (over 2) demonstrated that a nitrogen link was
compatible with potent MMP-13 activity and encour-
aged us to pursue the proposed N-linked spirocyclic
derivatives.
The first cyclic variant examined was spiro-lactam 4
(Table 2),30 a compound that is structurally similar to
a series of spirocyclic lactams that have since been dis-
closed by a research group at Bristol-Myers Squibb.
The potency of this compound corroborated their earlier
reported findings.20 The fact that 4 and 3 were roughly
equipotent and showed similar selectivity confirmed
the original hypothesis that changing from an acyclic
to a cyclic linker could be a productive strategy. While
these compounds had lost 5–6· potency relative to the
original ethoxyethyl analog 1, a larger problem of solu-
tion stability with the spirocyclic lactam systems was dis-
covered. Exposing these analogs to PBS (pH 7.2) at
25 ꢁC caused rapid decomposition of the parent analog
(t1/2 = 3.8 days). We reasoned that the decomposition
could be due to lactam ring opening, and thus examined
a range of other possible spirocyclic motifs (Table 2).
The spiropyrrolidine series was found to be stable in
solution (t1/2 > 1000 days, for 10b tested as a surrogate
for 10a), which supported our hypothesis that electronic
destabilization of the pyrimidinetrione caused solution
instability. While slightly less potent than acyclic analog
1, 10a was more potent than any other nitrogen-linked
analog (cyclic or acyclic) containing a simple terminal
fluorine atom. In the overall comparison of 1 and 10a,
the slight drop in potency (2·) was reasonably balanced
by a slight drop in lipophilicity (clogP drops by
ꢀ0.25 U), providing opportunity for further optimiza-
tion. While the pyrrolidine did not display an inherent
improvement in selectivity, we felt that optimization to
improve selectivity by extension of the P10group, and
the proper placement of heteroatoms within that ex-
tended tail was possible.
Unfortunately, most of these systems were less potent
than lactam 4. Changing the lactam to a cyclic sulfon-
amide produced compound 5, which was approximately
40-fold weaker than the original lactam. Substitution of
the original five membered lactam with gem-dimethyl
groups gave 6 which was twofold weaker than the
unsubstituted lactam. These analogs were also less stable
in solution that the original lactam. The addition of a
single methylene unit to form the six membered lactam
7 resulted in a threefold drop in potency. Both methyl-
To this end, the fluorine atom at the terminal phenyl
ring was replaced by more elaborate aryl–heteroaryl sys-
tems which had already provided potent and selective
inhibitors of MMP-13 in related, acyclic phenyl oxa-
zole1,31 and benzimidazole systems.32 In these com-
pounds, the spirocyclic pyrrolidine modification gave
modest (5–10·) increases in potency, relative to the acy-
clic, oxygen-linked analogs (Table 3). In general, high
levels of selectivity observed in the acyclic analogs for
MMP-12 and MMP-8 translated to comparably high
levels in the spirocyclic pyrrolidine system.33,34 This
was not surprising, since the extended P10group in this
system should be positioned to contact the same vari-
able loop at the base of the S10pocket which is likely
responsible for the observation of selectivity in the acy-
clic system.1 Unfortunately, the same was not true for
MMP-2 selectivity. MMP-2 selectivity was somewhat
compromised in the spirocyclic analogs. In several cases
(see compounds 14, 16, and 20) the selectivity ratio
Table 1. MMP-13 potency and selectivity for acyclic nitrogen
replacement analogs
Compound MMP-13 MMP-2 selectivity MMP-12 selectivity
IC50 (nM) (X-fold)
(X-fold)
1
2
3
0.6
8.9
2.9
8.3
16.6
14.7
46.5
7.1
10.7

K. D. Freeman-Cook et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6529–6534
Table 2. Various spirocyclic linkers
6531
Compound
Structure
MMP-13
IC50 (nM)
MMP-2 selectivity
(X-fold)
MMP-12 selectivity
(X-fold)
t1/2 solution stability
(days)
O
O
HN
N
O
4
3.49
16.4
7.39
13.6
9.40
16.1
13.8
8.92
5.83
23.2
2.09
17.6
86.5
21.5
14.2
33.6
22.0
3.8
F
F
N
N
O
N
H
O
O
O
O
S O
HN
N
5
138
1.1
O
N
H
O
O
O
HN
6
7.33
11.7
15.1
12.0
1.57
0.6
2.8
N
O
F
F
N
N
O
N
H
O
O
O
O
HN
N
O
7
ND
ND
ND
ND
>1000
O
N
H
H
N
O
O
HN
8
N
O
F
N
O
N
H
O
O
N
O
HN
9
N
O
F
F
N
N
O
N
H
O
O
O
HN
N
O
10a
10b
O
N
H
O
HN
N
O
Br
N
O
N
H
O
Scheme 1. Synthesis of spiropyrrolidine 10a.
dropped below the desired 100· threshold for progres-
sion through our screening cascade. Within the 4-phe-
nyl-oxazole series, SAR suggested that MMP-2
selectivity at the desired 100-fold level was only attain-
able with substituents in the para-position.
In the benzimidazole series (compounds 22, 24, and 26)
the spirocyclic linker still provided a 5–10· potency in-
crease. In this subseries, however, the selectivity trends
were different. It was no longer difficult to achieve high
levels of MMP-2 selectivity, and MMP-8 selectivity was

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K. D. Freeman-Cook et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6529–6534
Table 3. Spirocyclic pyrrolidines versus oxygen-linked ethoxyethyl analogs
O
OEt
O
HN
N
O
HN
O
N
O
N
H
O
N
H
O
O
O
Series B
Series A
Compound
R
Series
MMP-13 (nM)
MMP-2 (X)
MMP-12 (X)
MMP-8 (X)
1
10
A
B
0.59
1.6
9
6
48
34
ND
ND
F
N
N
11
12
A
B
0.68
0.12
400
127
568
1198
237
312
F
O
13
14
A
B
0.93
0.16
537
67
849
ND
269
ND
O
F
N
15
16
A
B
0.35
0.09
273
32
906
ND
128
ND
O
F
N
N
17
18
A
B
0.43
0.05
444
137
394
931
247
303
CN
O
O
19
20
A
B
0.52
0.11
31
15
133
ND
156
ND
CN
N
21
22
A
B
0.49
0.11
280
252
99
107
643
273
N
H
N
23
24
A
B
0.96
0.1
150
552
39
85
438
349
N
H
Cl
F
N
25
26
A
B
0.4
0.08
353
238
147
167
648
ND
N
H
also attainable. Now, MMP-12 selectivity became more
challenging (similar to the acyclic analogs 21, 23, and
25). While the use of the spirocyclic linker did provide
modest increases in selectivity, these were not always en-
ough to meet our goal of 100-fold for progression
through our entire screening cascade.
an IC50 of 12 nM.35 Compound 12 also performed very
well in our in vivo hamster model of direct intraarticular
injection of MMP-13 into the knee joint (>80% inhibi-
tion at 10 mg/kg po).36
Owing to its positive attributes, 12 was chosen to test the
hypothesis that a selective inhibitor of MMP-13 from
this spirocyclic series could avoid the MSS side effect.
Thus, 12 was advanced to a 14-day rat fibroplasia study,
a surrogate for the production of MSS in humans.37 No
acute toxicity was observed at doses of 30, 100, 300, and
800 mg/kg bid. At the highest two doses (300 and
800 mg/kg bid) comparable Cmax were obtained (63
and 52 lg/mL, respectively). Histological examination
revealed one instance of fibroplasia in each of these
groups. Whether this fibroplasia resulted from the high
Cmax causing inhibition of MMP-2 or -9 (each of which
compound 12 was ꢀ100· selective for), a combination
of both, or another unidentified MMP has not been
determined.
Given the selectivity and potency in this series, a number
of compounds were progressed to rat pharmacokinetic
studies. Among these, 12 was found to have an excellent
PK profile (Clp 3.9 mL/min/kg, Vdss 1.3 L/kg, t1/2 4.5 h).
When compared to the corresponding analog in the acy-
clic series, these spirocyclic analogs generally gave both
increased volume and clearance, the net effect of which
resulted in a very similar t1/2 value. As with the oxy-
gen-linked analogs, high oral absorption is obtained
when these compounds are dosed as the sodium salt.
Compound 12 is very effective at preventing the
MMP-13 induced in vitro degradation of bovine nasal
cartilage (as measured by hydroxyproline release) with

K. D. Freeman-Cook et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6529–6534
6533
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28. Concurrent with our work, a group at Bristol-Myers
Squibb was also exploring spirocyclic pyrimidinetrione
lactam analogs, their work was reported in 2005. See Ref.
20 for details.
29. Synthesis details for compounds 1–3. Compound 1: see
Ref. 2. Compound 2: 2-chloro-5-nitropyridine and 4-
fluorophenol are reacted in the presence of sodium
hydroxide to form 2-(4-fluorophenoxy)-5-nitropyridine.
The nitro group is then hydrogenated to form 6-(4-
fluorophenoxy)pyridin-3-amine. The resulting aniline is
subjected to diazotization, displacement by acetate, and
hydrolysis to produce 6-(4-fluorophenoxy)pyridin-3-ol.
This phenol is coupled directly to 5-bromo-5-(2-ethoxy-
ethyl)pyrimidine-2,4,6-trione according to procedures
found in Ref. 2 to form compound 2. Compound 3:
6-(4-fluorophenoxy)pyridin-3-amine is reacted with
5-bromo-5-(2-ethoxyethyl)pyrimidine-2,4,6-trione, as in
Ref. 2 to form compound 3.
30. Synthesis details for compounds 4–9: compounds 4–9 were
prepared according to schemes described in: Bronk, B. S.;
Noe, M. C.; Wythes, M. J.; Preparation of 1-aryl-1,7,9-
triazaspiro[4.5] decanetetraones and analogs as metallo-

6534
K. D. Freeman-Cook et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6529–6534
proteinase inhibitors. PCT Int. Appl. WO 02/034753 A2,
May 2, 2002.
31. Synthesis details for compounds 11, 13, 15, 17, and 19: all
of the above compounds were prepared according to
procedures found in Ref. 1.
32. Synthesis details for compounds 21, 23, and 25: substi-
tuted benzimidazoles (4-(4-(1H-benzimidazol-2-yl)phenoxy)
phenols) were prepared by reaction of 4-(4-hydroxyphen-
oxy)benzaldehyde (see Ref. 38) with appropriately substi-
tuted bis-anilines in the presence of FeCl3 and O2 (see Ref.
39). The resulting extended phenols were each reacted
according to procedures found in Ref. 2 to produce
compounds 21, 23, and 25.
34. Synthesis details for compound 22, 24, and 26: for
22, diethyl 1-(6-(4-iodophenoxy)pyridin-3-yl)pyrrolidine-
2,2-dicarboxylate is reacted in a Stille coupling with
vinyltributyltin, and the resulting olefin is cleaved with
osmiumtetroxide and sodium periodate to provide diethyl
1-(6-(4-formylphenoxy)pyridin-3-yl)pyrrolidine-2,2-dicar-
boxylate. This aldehyde is reacted with 1,2-diaminoben-
zene using similar procedures as given for the synthesis
of compounds 21, 23, and 25 to form diethyl 1-(6-(4-(1H-
benzimidazol-2-yl)phenoxy)pyridin-3-yl)pyrrolidine-2,2-
dicarboxylate. Treatment of this diester with urea and
sodium ethoxide produced 22. For (24), the same steps are
performed, but using 1,2-diamino-4-chlorobenzene. For
(26), the same steps are performed, but using 1,2-diamino-
4-fluorobenzene.
33. Synthesis details for compounds 12, 14, 16, 18, 20:
(12) 4-(4-fluorophenyl)oxazole is reacted with n-BuLi,
transmetalated with zinc, and then subjected to
a
35. Milner, J.; Elliot, S.-F.; Cawston, T. Arthritis Rheum.
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Stukenbrok, H.; Milici, A. Osteoarthritis Cartilage 2000,
8, 366.
37. Renkiewicz, R.; Qiu, L.; Lesch, C.; Sun, X.; Devalaraja,
R.; Cody, T.; Kaldjian, E.; Welgus, H.; Baragi, V.
Arthritis Rheum. 2003, 48, 1742.
palladium-mediated (Negishi) coupling with diethyl
1-(6-(4-iodophenoxy)pyridin-3-yl)pyrrolidine-2,2-dicarbox-
ylate (prepared by analogy to the corresponding 4-
fluorophenoxy derivative shown in Scheme 1). The
resulting diester is treated with urea and sodium
hydride in DMSO to produce 12. For (14), the same
steps are performed using 4-(2-fluorophenyl)oxazole as
a
starting material. For (16), the same steps are
38. Desai, R.; Han, W.; Metzger, E.; Bergman, J.; Gratale, D.;
MacNaul, K.; Berger, J.; Doebber, T.; Leung, K.; Moller,
D.; Heck, J.; Sahoo, S. Bioorg. Med. Chem. Lett. 2003, 13,
2795.
39. Singh, M.; Sasmal, S.; Lu, W.; Chatterjee, M. Synthesis
2000, 10, 1380.
performed using 4-(3-fluorophenyl)oxazole as a starting
material. For (18), the same steps are performed using
4-(oxazol-4-yl)benzonitrile as a starting material. For
(20), the same steps are performed using 3-(oxazol-4-
yl)benzonitrile as a starting material.