Pyran-containing sulfonamide hydroxamic acids: Potent MMP inhibitors that spare MMP-1

Article abstract of DOI:10.1016/j.bmcl.2004.04.083

The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P₁′ groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.

Full text of DOI:10.1016/j.bmcl.2004.04.083

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3389–3395
Pyran-containing sulfonamide hydroxamic acids: potent MMP
inhibitors that spare MMP-1
Lawrence A. Reiter,* Ralph P. Robinson, Kim F. McClure, Christopher S. Jones,
Matthew R. Reese, Peter G. Mitchell, Ivan G. Otterness, Marcia L. Bliven, Jennifer Liras,
Santo R. Cortina, Kathleen M. Donahue, James D. Eskra, Richard J. Griffiths,
Mary E. Lame, Arturo Lopez-Anaya, Gary J. Martinelli, Shunda M. McGahee,
Sue A. Yocum, Lori L. Lopresti-Morrow, Lisa M. Tobiassen and
Marcie L. Vaughn-Bowser
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA
Received 25 March 2004; revised 23 April 2004; accepted 27 April 2004
Available online
0
Abstract—The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1 groups is described. The
compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the
series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-
clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.
Ó 2004 Elsevier Ltd. All rights reserved.
Therapeutically useful inhibitors of the various matrix
metalloproteases (MMP’s) have been sought for over
30 years. The disclosure of the sulfonamide hydroxa-
mate CGS-27023A in 1994 revolutionized this pursuit.1
Prior to this time, research efforts focused on peptide-
like, hydroxamic acid-containing inhibitors that suffered
not only from rapid metabolism of the hydroxamic acid
but also from enzymatic cleavage of the two or three
amide bonds typically present in this class of inhibitors.2
The metabolic instability of these peptide-like com-
pounds together with their sub-optimal physical prop-
erties––high molecular weight and low aqueous
solubility––diminished their prospects for becoming
useful therapeutic agents. The sulfonamide hydroxa-
mate series eliminated most of these issues with meta-
bolism of the hydroxamic acid remaining as the key
problem. The vast number of publications and patents
on related compounds that have appeared since 1994
attest to the impact the disclosure of the sulfonamide
hydroxamate series has made on this research area.3
N
O
O
N
HOHN
S
O
OCH3
CGS-27023A
Concurrent with the disclosure of CGS-27023A were
two other reports of critical importance to research in
the MMP field.4 The first of these was the identification
of MMP-13,5;6 a third collagenase, which has been
implicated to play a key role in the pathology of
osteoarthritis (OA). MMP-13 is present in OA cartilage
tissue in humans,5;7 turns over type II collagen,5;6 is co-
localized with cleaved type II collagen in OA cartilage
tissue,8 and degrades cartilage.9 The second critical re-
port related to side effects that were observed upon
dosing humans with broad spectrum (i.e., nonselective)
MMP inhibitors.10 These side effects, collectively termed
musculoskeletal syndrome (MSS), were postulated by us
and others11 to arise from the inhibition of MMP-1
owing to its presumed role in the normal turnover of
extracellular matrix in connective tissue.
Keywords: MMP; Collagenase; Hydroxamic acids.
* Corresponding author. Tel.: +1-860-441-3681; fax: +1-860-686-1176;
e-mail: reiterla@groton.pfizer.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.083

3390
L. A. Reiter et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3389–3395
The conjunction of these research findings led us, in our
efforts to identify compounds useful for treating OA, to
seek an MMP inhibitor from the sulfonamide hy-
droxamate series that potently inhibited MMP-13,
spared MMP-1, and which had metabolic stability
consistent with once or twice daily dosing in humans.
was later purged during the sulfonylation step in which
it is less reactive than the exo isomer. Cleavage of the
ester with TFA and conversion of the resultant acid to
the acid chloride was followed by coupling with bis-
TMS-hydroxylamine, prepared in situ, to yield, after
aqueous acid work-up, the hydroxamic acid.16 Esters of
many of the simple cycloalkyl amino acids were readily
available. In some cases, the corresponding methyl or
ethyl esters were employed with the appropriate substi-
tution of a saponification step to release the free acid.17
The synthesis of the symmetrical pyran utilized
bis(bromoethyl)ether in the first step.18 The chiral py-
rans and tetrahydrofurans were prepared starting with a
protected serine derivative19 followed by appropriate
modification of the substituents to form either five- or
six-membered rings.20 The hydroxamic acids could
alternatively be prepared by coupling of the intermedi-
ate acids with O-benzylhydroxylamine followed by hy-
drogenolysis.21
Sequence analysis and a homology model of MMP-13
constructed from an MMP-1 X-ray crystal structure
indicated that MMP-13 belongs to the set of MMPs that
0
have a deep S1 pocket. X-ray crystal structures of both
enzymes subsequently confirmed this.12 Since MMP-1
0
has a shallow S1 pocket, obtaining selectivity over
0
MMP-1 (and other shallow S1 pocket enzymes) was
0
expected to be possible by increasing the size of the P1
substituent in the inhibitor. Furthermore, we reasoned
that sterically hindering the hydroxamic acid would re-
duce metabolism of this functionality.
Scheme 1 outlines the synthesis of 41 as an illustration of
the methods used to prepare target compounds. Alkyl-
ation of the benzophenone imine of tert-butyl glycine13
with the bis-tosylate14 yielded the [3.2.1]oxabicyclic
system in good yield. In this case, a mixture of diaste-
reomers was obtained whereas, in the monocyclic cases,
only a single isomer would result from this reaction.
Subsequent deprotection with hydroxylamine efficiently
yielded the amine.15 The minor endo diastereomer was
generally not separated after either of these steps since it
Our initial investigations showed that a substituent on
the sulfonamide nitrogen of CGS-27023A is not neces-
sary for potent inhibition of MMP-13. Thus, 1 (Table 1)
displays potent MMP-13 inhibition and is reasonably
selective over MMP-1.22 Increasing the bulk adjacent to
the hydroxamic acid to sterically inhibit metabolism of
this group diminishes both MMP-13 and MMP-1
activities and reduces selectivity (2–4). However, these
0
analogs do not take advantage of the deeper S1 pocket
O
Ph
Ph
O
N
Ph
N
tBuO
O
t-BuO
Ph
TsO
OTs
LiN(TMS) / DMF / 115°C
2
48%
4:1 mixture of
O
diastereomers
N-exo (major) isomer
NH2OH.HCl
EtOH / reflux
78%
ArSO Cl
2
cat DMAP
iPr NEt
2
O
O
H
N
O
NH2.HCl
CH Cl
2
2
t-BuO
t-BuO
S
O
F
mixture of
diastereomers
O
62%
O
O
TFA/CH Cl
2
2
87%
O
O
H
N
H
N
O
O
HO
N
H
S
O
F
HO
S
O
F
O
O
1) (COCl)
cat. DMF
2
O
O
41
CH Cl
2
2
2) TMSONHTMS
(generated in situ)
pyridine
crystalline solid
3) H O+
3
Scheme 1. Synthesis of 41.

L. A. Reiter et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3389–3395
Table 1. SAR of a,a-disubstituted hydroxamic acids
3391
O
H
N
O
HOHN
S
O
OR1
C logP
Substitution
R1
MMP-13
IC50 (nM)
MMP-1
IC50 (nM)
Ratio
hLH Era
hLM Era
rLM Era
Hamster % inh @
30 mg/kg po
CGS-27023A
18
2.5
7
1.59
0.97
––
––
––
––
––
––
––
H
1
2
3
–CH3
–CH3
–CH3
1.7
170
100
––
17
50
1100
900
65
18
0.35
1.10
––
––
––
––
––
––
––
––
4
–CH3
49
550
11
1.66
––
––
––
––
5
6
4-F–Ph–
4-F–Ph–
0.90
0.93
1200
500
1300
540
2.71
2.35
0.55
0.48
<0.37
<0.34
<0.42
0.47
56%
56%
7
8
4-F–Ph–
4-F–Ph–
0.53
0.90
280
65
530
72
2.91
3.47
0.75
0.75
<0.39
0.33
0.32
0.40
51%
23%
9
4-F–Ph–
4-F–Ph–
0.97
0.75
330
420
340
560
4.03
1.56
0.70
0.32
0.32
39%
68%
10
<0.30
<0.20
<0.20
O
a hLH: extraction ratio human liver hepatocytes, hLM: human liver microsomes, rLM: rat liver microsomes, see Ref. 27.
0
of MMP-13. Increasing the size of the P1 group to 4-
fluoro-phenoxy to take advantage of the deeper pocket
yielded 5, 8, and 9, which display increased MMP-13
potency (IC50 < 1 nM) and, in the case of 5 and 9, high
selectivity (>100-fold). Compounds containing the
smaller cyclopropyl and cyclobutyl rings, 6 and 7
respectively, also display good potency and selectivity.
The pyran analog 10, which was prepared in an attempt
to identify compounds with improved solubility (lower
C logP than 5–9), was found to be as active and selective
as other compounds in the series. While the solubility of
this compound is not substantially different from that of
the other analogs (all >65 lg/mL), unexpectedly, 10 was
found to be significantly more stable when incubated
with human liver hepatocytes, having an extraction ratio
(Er) of <0.30. Its somewhat improved potency over the
cycloalkyl derivatives in our in vivo hamster model23
(52% inhibition at 15 mg/kg po) is possibly a manifes-
tation of its improved metabolic stability. These findings
led us to continue our investigation of the SAR of the
series by focusing on pyrans and closely related com-
pounds.
In this exploration of the SAR, we initially examined the
effect of changing the substitution pattern on the ter-
minal P1 phenoxy ring (Table 2). The unsubstituted
0
analog 11, is somewhat less potent than the 4-fluoro-
phenoxy analog and displays a lower potency in our in
vivo hamster model. Such a decrease in potency in the
hamster model between a 4-substituted phenoxy analog
and the corresponding unsubstituted derivative had
been observed in other series. We believe this reflects
rapid metabolism at C-4 of the phenoxy group. Altering
the position of the fluorine atom on the phenoxy group
does not make a significant difference to potency (12 and
13). Compounds 12 and 13 are stable when incubated
with human liver microsomes (data not shown); how-
ever, they are notably less stable than 10 in a rat
microsome preparation, again emphasizing the meta-
bolic benefit of blocking C-4 of the phenoxy group with
a substituent. Chloro substituents at C-2 (14) and C-3
(15) decrease the potency significantly indicating that
0
although the S1 pocket may be deep, it is also relatively
narrow––able to accommodate ortho or meta fluoro but
not chloro groups. Compounds containing 4-chloro

3392
L. A. Reiter et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3389–3395
0
Table 2. SAR of P1 residues on pyran hydroxamic acids
O
H
N
O
HOHN
S
O
X
ZR1
Ratio
X
Z
R1
MMP-13
IC50 (nM)
MMP-1
IC50 (nM)
C logP
Hamster % inh
@ 15 mg/kg po
rLM Era
11
12
13
10
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
Ph–
2-F–Ph–
1.5
0.64
0.56
0.75
9.7
4.6
1.2
0.87
1.7
210
5.0
6.5
19
490
180
330
280
1960
560
180
850
270
900
2820
23
1.37
1.36
1.56
1.56
1.97
2.13
2.13
1.34
1.01
2.55
2.55
0.96
1.10
1.10
1.67
0.57
0.22
0.22
0.74
0.96
1.40
1.01
2.59
0.33
19%
52%
48%
0.57
0.61
3-F–Ph–
4-F–Ph–
1100
420
<0.20
0.53
0.79
2-Cl–Ph–
3-Cl–Ph–
4-Cl–Ph
1700
3900
320
<0.20
0.43
0.93
4-CH3O–Ph–
4-NC–Ph–
1-Naphthyl–
2-Naphthyl–
Benzyl–
780
4800
4900
3900
5400
9600
8800
6500
12,000
550
0.67
780
830
500
370
590
920
22
11%
0%
2-F-benzyl–
3-F-benzyl–
4-F-benzyl–
2-Pyridyl–
3-Pyridyl–
4-Pyridyl–
5-F-2-Pyridyl–
5-Cl-2-Pyridyl–
4-F–Ph
24
11
13
25
5.7
14
12,000
3800
1400
5900
200
2100
270
930
1280
45
50%
<0.20
0.45
1.5
4.6
4.4
1.5
2.0
31%
26%
51%
6%
––
O
O
4-F–Ph
4-F–Ph–
4-F–Ph–
750
550
500
280
SO2
a rLM: extraction ratio rat liver microsomes, see Ref. 27.
(16), 4-methoxy (17), and 4-cyano (18) groups are about
as potent as 10. However, despite having C-4 blocked,
only the 4-chloro derivative displays appreciable stabil-
ity in rat microsomes with the C-4 methoxy and cyano
groups apparently being subject to another mode of
metabolism. Larger groups, such as naphthyl or benzyl
diminish activity and substitution on the benzyl groups
decrease potency even further (19–24). Of the two
naphthyl derivatives, the more ‘linear’ 2-naphthyl ana-
in the hamster assay and stability in rat liver micro-
somes, we continued our work focusing on compounds
containing 4-fluoro- and 4-chlorophenoxy P1 side
chains.
0
Two approaches were taken toward further improving
the characteristics of the series. One was to move the
heteroatom of the pyran ring closer to the hydroxamic
acid. Since introduction of a heteroatom into the origi-
nal cycloalkyl series led to the metabolically improved
pyran series, we postulated that placing the heteroatom
even closer to the site of metabolism could lead to fur-
ther reduction in turnover. The second approach was to
place additional steric hindrance around the hydroxamic
acid by incorporating a bicyclic system.
0
log is the more potent, again indicating that the S1
pocket is deep and narrow. Replacing the phenoxy
group with a heterocycle, 2-, 3-, or 4-pyridinyloxy, is
also detrimental to activity whether the pyridine is
substituted or not (25–29). The diminished activity of
these pyridines presumably reflects the lower compati-
bility of the relatively hydrophilic pyridyl groups with
0
the hydrophobic S1 pocket (see C logPs in Table 2).
In the first of these, both pyrans and tetrahydrofurans
were prepared. These chiral analogs of 10 and 16 display
enantiospecific differences in that the S isomers, 36, 38,
and 40 are all somewhat more potent than the corre-
sponding R isomers 35, 37, and 39 (Table 3). Modeling
suggested that this may be due to differences in the
interactions of the pyran or furan oxygen atom with the
water network in the P1 region of the protease. Al-
though some attributes of these compounds are im-
proved over those of 10 and 16, on balance none of the
compounds is clearly superior. For example, the in vivo
characteristics of 35 are quite promising with the half-
lives in rats and dogs being improved over those of the
Other structural alterations as represented by the thio-
phenoxy analog 30 or the biphenyl derivative 31 lead to
a loss of potency presumably owing to the altered
0
geometry of the P1 side chain. Replacing the pyran with
a thiopyran as in 32 is tolerated but at the cost of a
significant increase in the log P (2.59) and a decrease in
stability in the rat microsome preparation. Nevertheless,
the compound shows good activity in the hamster
model. The corresponding sulfone 33 is less lipophilic
but is also less potent as an MMP-13 inhibitor
and shows very weak activity in the hamster
model. Owing to the combination of potency, activity

Table 3. SAR of chiral pyran, chiral tetrahydrofuran, and bicyclic analogs
O
H
N
O
H
N
O
O
H
N
O
O
H
N
O
O
O
O
HOHN
S
O
HOHN
S
O
HOHN
S
O
HOHN
S
O
O
OR1
O
OR1
OR1
OR1
Achiral 6-membered ring series
Chiral 5-membered ring series
Chiral 6-membered ring series
6-5 Bicyclic ring series
Ring size/ MMP-13
stereochem/X IC50 (nM)
MMP-1
IC50 (nM)
Ratio
hLH Era
hLM Era rLH Era
rLM Era
Hamster
% inh (@
15 mg/kg)
Rat PKb
Dog PKb
Vss t1=2
Clp
52.6
Vss
t1=2
F
Clp
F
R1 ¼ 4-X–Ph
6/––/F
10
16
34
35
36
37
38
39
40
41
42
43
0.75
1.2
420
320
290
350
59
560
270
520
350
170
920
960
930
700
300
280
450
<0.30
<0.20
0.41
0.33
0.08
0.23
0.43
0.36
<0.20
<0.20
<0.27
<0.34
0.37
52%
48%
1.9
2.1
3.2
1.6
0.9
3.6
3.9
4.9
29
72
––
31
10.3
8.0
1.6
1.8
3.6
3.1
6.5
52
62
––
––
6/––/Cl
6/R/F
6/R/Cl
12.7
21.8
7.9
6.0
5.8
0.56
1.0
0.90
0.60
<0.28
<0.33
19.2
10.2
50%
11.0
6/S/Cl
5/R/F
0.35
1.3
1200
740
870
260
150
180
1500
<0.22
0.36
0.34
5/S/F
5/R/Cl
0.77
0.93
0.37
0.50
0.65
3.3
205
142
39.4
5.8
––
0.8
0.6
1.5
1.1
7.4
––
––
––
90
39
5/S/Cl
<0.42
<0.30
1.5
1.5
2.8
6–5/exoc/F
6–5/exoc/Cl
6–5/endoc/F
<0.29
<0.48
<0.30
54%
71%
27.7
8.9
7.8
1.5
6.5
86
a hLH: extraction ratio human liver hepatocytes, hLM:––human liver microsomes, rLH: rat liver hepatocytes, rLM: rat liver microsomes, see Ref. 27.
b Clp: mL/min/kg; Vss: L/kg, t1=2: h, F : %.
c exo: sulfonamide and ring oxygen are syn, endo: anti.

3394
L. A. Reiter et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3389–3395
achiral analogs; however, the human liver hepatocyte
extraction ratio is significantly higher.
References and notes
1. MacPherson, L. J., Parker, D. T. European Patent 0 606
046, July 13, 1994; O’Byrne, E. M.; Parker, D. T.; Roberts,
E. D.; Goldberg, R. L.; MacPherson, L. J.; Blancuzzi, V.;
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Inflamm. Res. 1995, 44(Supl 44), S117–S118; MacPherson,
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S.; Blancuzzi, V.; Wilson, D.; O’Byrne, E. M.; Ganu, V.;
Parker, D. T. J. Med. Chem. 1997, 40, 2525.
In the second approach, both diastereomers of the
bicyclic system were prepared with the exo isomer dis-
playing the better potency (41 vs 43). The potency,
selectivity, stability in in vitro metabolism assays and the
in vivo attributes of the 4-fluorophenoxy analog 41 are
very similar to those of 10, plus 41 has the advantage of
having better bioavailability in rats and dogs.
Compounds 10 and 41 fulfilled our goal of identifying a
sulfonamide hydroxamate that is a potent MMP-13
inhibitor (IC50s 0.75 and 0.50 nM, respectively), spares
MMP-1 (560-fold and 300-fold, respectively) and is
projected to have once or twice daily dosing in humans
(t1=2 projected by allometric scaling: 8–13 and 5–10 h,
respectively). As a result, both 10 and 41 were advanced
into development. Compound 10 was first examined in a
two-week rat toxicology study in order to determine its
capacity for producing fibroplasia, with this assay acting
as a surrogate for the likelihood of a compound pro-
ducing MSS in humans.24 It did not display fibroplasia
in this two-week study and was therefore advanced into
clinical trials. Two-week safety trials in normal volun-
teers revealed no side effects related to MSS. However,
after dosing for four to six weeks in OA patients,
exposure related MSS was observed.25 Concurrent 90-
day safety studies in rats revealed that with this long
exposure, 10 does produce fibroplasia. Likewise, con-
current two-week toxicology studies with 41 in rats
showed that this compound also produces fibroplasia.
These results led us to terminate the study of this series
of compounds and to conclude that inhibition of MMP-
1 alone is not responsible for the MSS side effect that has
been seen in humans with a variety of MMP inhibitors.
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appears to be exposure related with 10 producing this
effect only after many weeks while 41, which has sig-
nificantly higher bioavailability in rats, produces the
effect within two weeks. Since both 10 and 41 are fairly
nonselective inhibitors of MMPs other than MMP-1
(see Table 4), just which of these is responsible for the
development of side effects in humans and pathology in
rats remains unclear. Although MSS was observed with
our MMP-1 sparing MMP-13 inhibitor, the reduced
production of the neo-epitope formed by the cleavage of
type II collagen by MMP-13 in OA patients treated with
1026 encourages us to seek MMP-13 inhibitors that
possess higher degrees of selectivity over other MMPs.
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Table 4. MMP activities of 10 and 41 IC50s (nM)
10
41
MMP-13
MMP-1
MMP-8
MMP-2
MMP-9
MMP-3
MMP-12
MMP-14
0.75
420
1.4
1.6
12
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0.26
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ꢀ
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16
4.2
––
0.24
7.4
––

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