β-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: Part 2. Optimization of α-amino substituents

Article abstract of DOI:10.1016/j.bmcl.2007.11.129

The introduction and the optimization of an α-amino substituent based on a series of α-hydroxy-β-N-biaryl ether sulfonamide hydroxamates is described. The modification leads to a new series of MMP-2/MMP-9 inhibitors with enhanced inhibitory activities and

Full text of DOI:10.1016/j.bmcl.2007.11.129

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1140–1145
b-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase
inhibitors: Part 2. Optimization of a-amino substituents
Shyh-Ming Yang,* Robert H. Scannevin, Bingbing Wang, Sharon L. Burke,
Zhihong Huang, Prabha Karnachi, Lawrence J. Wilson, Kenneth J. Rhodes,
Bharat Lagu and William V. Murray
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, NJ 08512, USA
Received 10 October 2007; revised 28 November 2007; accepted 30 November 2007
Available online 5 December 2007
Abstract—The introduction and the optimization of an a-amino substituent based on a series of a-hydroxy-b-N-biaryl ether sulfon-
amide hydroxamates is described. The modification leads to a new series of MMP-2/MMP-9 inhibitors with enhanced inhibitory
activities and improved ADME properties. An efficacy study on reducing the ischemia-induced brain edema in the rat transient mid-
dle cerebral artery occlusion (tMCAo) model is also demonstrated.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Gelatinases, a sub-family of matrix metalloproteinases
(MMPs), include gelatinase A (MMP-2) and gelatinase
B (MMP-9). These enzymes are responsible for the deg-
radation of extracellular matrix proteins such as dena-
tured collagen, elastin, laminin, and fibronectin. The
up-regulation of MMP-2 and/or MMP-9 activity has
been implicated in a number of pathological events lead-
ing to cancer, inflammatory diseases, cardiovascular dis-
eases, and neurological disorders.1 Recent studies have
demonstrated that the gelatinase expression level and
activities increased markedly following an ischemic in-
sult.2 This results in vascular breakdown and increased
permeability of the blood–brain barrier (BBB) that ulti-
mately leads to edema, hemorrhaging, and significant
brain damage.3 Therefore, inhibiting MMP-2 and/or
MMP-9 activity as a potential treatment of acute ische-
mic stroke (IS) is highly desirable.4
rected toward the discovery of gelatinase inhibitors for
the potential treatment of acute IS. Compounds 3,
which also contain a N-biaryl ether unit, exhibited sig-
nificant activity for MMP-2/MMP-9, but lacked suitable
solubility and sufficient pharmacokinetic (PK) proper-
ties preventing further development.7 Herein we disclose
the introduction and the optimization of an a-amino
group that led to a new series of gelatinase inhibitors
with enhanced inhibitory activities and improved
ADME properties.8 An efficacy study on reducing the
ischemia-induced brain edema in the rat transient mid-
O
O
O
O
S
N
O
HN
N
Cl
NH
HO
O
N
H
O
O
Several cyclic amides (1)5 or sulfonamides (2)6 bearing a
biaryl or biaryl ether P10 moiety on the nitrogen atom
have been recently identified (Fig. 1). Inhibitors contain-
ing these substitution patterns have demonstrated excel-
lent inhibitory activities against MMPs and several have
been considered as potential drug candidates. We have
previously identified a novel series of a-hydroxy-b-sul-
fonamide hydroxamates (Fig. 1, 3) during a program di-
2
1
MMP-2: 0.4 nM (Ki)
MMP-9: 0.9 nM (Ki)
MMP-13: 1.2 nM (Ki)
OMe
MMP-2: 0.4 nM (Ki)
MMP-9: 0.7 nM (Ki)
MMP-13: 1.0 nM (Ki)
O
S
N
O
Me
HO
H
N
R1
HO
O
O
(S)-3
(S)-3a, R1= Me, MMP-2: 61 nM, MMP-9: 7.8 nM
(S)-3b, R1= Cl, MMP-2: 35 nm, MMP-9: 4.7 nM
Keywords: Gelatinase; Matrix metalloproteinase; MMP inhibitor;
Stroke; Hydroxamate.
Figure 1. Potent MMP inhibitors bearing a P10 moiety on the nitrogen
atom.
*
Corresponding author. Tel.: +1 609 409 3491; fax: +1 609 655
6930; e-mail: syang9@prdus.jnj.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.129

S.-M. Yang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1140–1145
1141
dle cerebral artery occlusion (tMCAo) model is also
described.9
ically to single-digit nanomolar range for MMP-2 and
sub-nanomolar for MMP-9. A similar improvement
was observed for (S)-8a (vs (S)-3c). Meanwhile, the chi-
rality of the a-position became critical in terms of po-
tency when the bulkier group was attached.12 For
example, the (S)-8b was 45- and 60-fold more potent
than its enantiomer ((R)-8b) against MMP-2 and
MMP-9, respectively. As expected the corresponding
carboxylic acid (S)-9 was inactive. In addition, the a-
amide substituent ((S)-12) exhibited similar activities
as the lead compound (S)-3a.
In an initial attempt to increase potency and improve
the ADME properties, a diverse set of substituents
was introduced to the a-position of the lead 3 by an
SN2 displacement of the activated hydroxyl group. The
synthesis of key intermediate (R)-6 with opposite config-
uration of the OH group began from the biaryl ether 4
in two steps, formation of the sulfonamide followed by
ring opening of the epoxide (Scheme 1).10 The activation
of the OH group with triflic anhydride gave (R)-7, which
could undergo a facile SN2 displacement reaction with
various amines.11 For example, compound (S)-8 bearing
a secondary or tertiary (cyclic or acyclic) amino group at
the a-position could be easily obtained from (R)-7 by an
SN2 displacement followed by a hydroxamate formation
sequence. The displacement of (R)-7 with isopropyl
amine followed by hydrolysis under basic conditions
gave the acid (S)-9. Treatment of (S)-7 with sodium
azide followed by Pd-catalyzed hydrogenation or direct
SN2 displacement of (S)-7 with ammonia in methanol
provided (S)-10, which was converted to (S)-11 and
amide (S)-12 using similar transformations as described
above.
On the other hand, increasing the size of the alkyl sub-
stituent to isobutyl ((S)-8c) or cyclopentyl ((S)-8d) had
only minimal influence on potency. Analogs containing
the pyridinylmethyl substituent (e.g., (S)-8e–f), that
adopted the same form as CGS-27023A,13 had compa-
rable activities with the exception of (S)-8g which was
10-fold less potent. Interestingly, the analogs containing
a benzyl group (e.g., (S)-8h–i) typically gave good po-
tency with approximately 16- to 28-fold selectivity for
MMP-9 over MMP-2. Moreover, the analogs bearing
an a-aniline type substituent, for example, (S)-8j–n, also
provided excellent inhibitory activities while retaining
the MMP-9 selectivity, particularly for those having
H-bonding acceptor capability at the meta-position
(e.g., F and OMe in (S)-8l and (S)-8n, respectively).
Compound (S)-8o showed decreased potency possibly
due to the steric influence of the naphthalene ring.
The inhibitory activities (IC50) against MMP-2 and
MMP-9 in comparison with lead compound 3 are com-
piled in Table 1. Initially, efforts were primarily focused
on analogs with a secondary amino group attached at
the a-position. In general, as observed with the original
lead 3, these compounds retained good activity for
MMP-2 and MMP-9 without inhibiting MMP-1
(IC50 > 10 lM). By simply changing the OH to a NH2
((S)-3a vs (S)-11) led to an 11- and 16-fold loss in po-
tency against MMP-2 and MMP-9, respectively. How-
ever, switching the OH to an alkylamino, such as
isopropylamino ((S)-8b), increased the potency dramat-
Since bulky substituents surrounding the hydroxamate
moiety may slow down its metabolism,14 the introduc-
tion of a tertiary amino group at the a-position was next
examined (Table 2). Based on several acyclic, tertiary
amino substituents tested, the combination of isopropyl
with several alkyl groups (e.g., (S)-8p–r) did not have a
beneficial effect and caused about 4- to 30-fold loss of
potency for MMP-2 and MMP-9. To our delight, cyclic
O O
S
O
O O
S
O
O
O
O O
S
O O
S
O O
S
HN
Me
HO
MeO
b
N
Me
MeO
N
Me
MeO
N
Me
N
H
O
N
Me
OH
TfO
H2N
NH
g or h
R1= Me
i,e
c
O
O
O
O
O
R1
5
R1
R1
d,f
Me
(R)-6
(S)-10
(S)-12
(R)-7
Me
e
a
d,e
O O
R1= Me
O
O
O
O O
S
O O
NH2
HO
S
HO
S
N
H
N
Me
HO
N
Me
N
H
N
Me
N
R2
NH
H2N
R3
O
O
O
O
R1
R1
(S)-8
(S)-9
4
(S)-11
Me
Me
Scheme 1. Reagents and conditions: (a) MeSO2Cl, pyridine, 0 ꢁC to rt, 1 h, 48–96%; (b) Method A: methyl (R)-glycidate, K2CO3, BnEt3NCl,
dioxane, 60–90 ꢁC, 55–91%; Method B: methyl (R)-glycidate, K2CO3, DMF, 80–100 ꢁC, 71–86%; (c) Tf2O, 2,6-lutidine, ꢀ20 to 0 ꢁC, 85–94%; (d)
R2NHR3, CH2Cl2, 0 ꢁC to rt, 40–96%; (e) HONH2ÆHCl, NaOMe, MeOH, 35–93%; (f) LiOH(aq), THF, rt, %; (g) i—NaN3, acetone, H2O, rt, 95%; ii—
H2, Pd/C, EtOAc, rt, 90%; (h) NH3 in MeOH (2 M), CH2Cl2, 0 ꢁC to rt, 2 h, 82%; (i) i-PrCOCl, 2,6-lutidine, CH2Cl2, rt, 1 h, 95%.

1142
S.-M. Yang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1140–1145
Table 1. IC50 of 3, 8a–o, 9, and 11–12 against MMP-2 and MMP-9
R1
R2NR3
Fold selectivity (MMP-2/MMP-9)
a
MMP-2 IC50 (nM)
a
MMP-9 IC50 (nM)
Compound
(S)-3a
(S)-3b
(S)-3c
(S)-8a
(R)-8b
(S)-8b
(S)-8c
(S)-8d
(S)-8e
(S)-8f
(S)-8g
(S)-8h
Me
Cl
—
—
61
35
7.8
4.7
14
7.8
7.4
9.9
3.8
5.7
7.7
8.8
5.9
5.3
6.1
3.6
28.4
CF3
CF3
Me
Me
Me
Me
Me
Me
Me
Me
—
i-PrNH
139
9.2
178
4.0
11
2.4
31
i-PrNH
i-PrNH
i-BuNH
0.52
1.3
1.7
1.8
2.8
23b
7.1
(Cyclopentyl)NH
(Pyridin-4-yl)CH2NH
(Pyridin-3-yl)CH2NH
(Pyridin-2-yl)CH2NH
PhCH2NH
10
9.5
17
83b
202b
Me
R
(S,R)-8i
(S,S)-8i
Me
Me
24
12
1.5
16.0
22.2
Ph
Ph
NH
Me
0.54
S
NH
(S)-8j
(S)-8k
(S)-8l
(S)-8m
(S)-8n
(S)-8o
(S)-9
Me
Me
Me
Me
Me
Me
—
PhNH
(4-F)PhNH
13
64
0.52
1.3
25.0
49.2
59.6
16.6
43.5
16.6
—
(3-F)PhNH
(3-Cl)PhNH
53
0.89
20b
333b
27
(3-MeO)PhNH
(Naphthylen-2-yl)NH
0.62
86b
>10 lMb
121
5.4
1.4 lMb
>10 lMb
670
—
—
—
(S)-11
(S)-12
—
—
5.5
13.0
70
a Values are means of at least two experiments.
b Single experiment.
amino substituents such as morpholine ((S)-8s) provided
similar potency to the isopropyl analog (S)-8a. Several
cyclic amines were examined, including substituted mor-
pholine, piperazine, piperidine, etc. ((S)-8t–z), and all
showed excellent activity in inhibiting both MMP-2
and MMP-9 in single-digit nanomolar range. However,
the cyclic amine bearing an extra phenyl ring at the 4-
position was unfavorable and caused the potency to
drop significantly as exemplified by (S)-8aa and (S)-
8bb. Further investigation by docking studies of these
analogs with a MMP-9 homology model revealed that
the cyclic amino substituents seem to be pointing to
the solvent area, whereas the benzyl ((S)-8h) and phenyl
((S)-8j) groups aligned closer to the S1 subsite. The
hydrophobic interaction of the phenyl or benzyl with
the S1 subsite may have contributed somewhat to the
selectivity for MMP-9 versus MMP-2. These observa-
tions may also explain the minor influence on potency
as well as the decreased MMP-9/-2 selectivity when a
cyclic amino group was attached.
a cyclic amino group at the a-center, such as ((S)-8ee),
was consistently greater than 250-fold more potent than
their corresponding R-enantiomer in both the MMP-2
and MMP-9 enzymatic assays.
Attempts to increase the stability of the hydroxamate
moiety by adding a substituent at the nitrogen atom were
briefly examined. The coupling of acid (S)-13 with O-trityl
protected hydroxylamine provided intermediates (S)-14,
which could undergo alkylation followed by trifluoroace-
tic acid (TFA) deprotection to furnish the analogs (S)-16
(Scheme 2). N-Methylation [compound (S)-16a
(R = Me)] significantly decreased the potency to 447 nM
and 160 nM for MMP-2 and MMP-9, respectively. How-
ever, (S)-16b (R = i-Bu) gained some potency back
(261 nM and 88 nM for MMP-2 and MMP-9, respec-
tively). It is likely that the isobutyl group provided some
hydrophobic interaction with the S1 subsite.
Several potent compounds were selected to evaluate
their PK (rats) and other ADME properties (Table 3).
The compounds bearing a secondary amino group at
the a-position, such as (S)-8b and (S)-8l, showed rela-
tively poor microsomal stabilities (RLM < 9 min),
which was reflected in the PK profile (low plasma expo-
sure (AUC) and high clearance level (CL)). Among the
compounds tested, (S)-8ee provided a better PK profile,
though the half-life in RLM was only 10 min. The ana-
logs containing an a-cyclic amino group, for example,
(S)-8s and (S)-8ee, exhibited great water solubility
(>70 lg/mL) at both pH 2.0 and pH 7.0. Additionally,
these compounds also showed low protein binding
Additionally, it has been previously observed in com-
pounds 3 that analogs with Me and Cl substituents
(R1) provided slightly better potency than those with
CF3.7 Indeed, a similar trend was also obtained when
the cyclic amines, such as morpholine and cis-dim-
ethylmorpholine, were incorporated at the a-position.
In general, these analogs (R1 = Me or Cl) exhibited
excellent potency and were ca. 2- to 4-fold more potent
than those with R1 = CF3 ((S)-8cc, (S)-8ee and (S,cis)-
8dd, (S,cis)-8ff vs (S)-8s and (S,cis)-8t, respectively). In
addition, the S-enantiomer of the compounds bearing

S.-M. Yang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1140–1145
Table 2. IC50 of 8 with tertiary a-alkylamino substituents
1143
R1
R2NR3
MMP-2 IC50 (nM)
MMP-9 IC50 (nM)
Fold selectivity (MMP-2/MMP-9)
a
a
Compound
(S)-8a
(S)-8p
(S)-8q
(S)-8r
CF3
CF3
CF3
CF3
i-PrNH
i-PrNMe
9.2
2.4
8.8
68b
29b
3.8
2.7
4.1
9.0
24
i-PrNCH2Ph
i-PrNCH2CH2NHCbz
281b
262b
(S)-8s
CF3
CF3
CF3
CF3
9.3
5.6
9.9
8.6
2.9
1.1
3.2
4.8
3.2
5.1
3.1
1.8
N
O
(S,cis)-8t
(S)-8u
(S)-8v
N
O
O
S
O
N
N
N
O
N
S
O
O
(S)-8w
(S)-8x
(S)-8y
CF3
CF3
CF3
4.8
7.6
5.7
1.7
2.3
1.9
2.8
3.3
3.0
N
N
N
OH
O
(S)-8z
CF3
CF3
5.5
2.5
2.2
2.7
N
N
NHMe
(S)-8aa
47b
17b
(S)-8bb
(S)-8cc
CF3
Cl
119b
5.5
256b
2.0
2.7
2.8
N
N
N
O
Cl
(S,cis)-8dd
(R)-8ee
Cl
N
O
2.5
0.46
295b
1.9
5.4
4.5
2.7
4.1
Me
Me
Me
1318b
5.2
N
N
N
O
O
O
(S)-8ee
(S,cis)-8ff
2.8
0.68
a Values are means of at least two experiments.
b Single experiment.
(PB), 58% and 74% for (S)-8ee and (S)-8s, respectively.15
Finally, the enzyme selectivity of (S)-8ee with selected
MMPs was briefly evaluated, which provided the IC50
values of >10 lM, 137 nM, and 3.5 nM for MMP-1,
MMP-3, and MMP-13, respectively.
cally increased brain water content (i.e., edema) in the
ischemic hemisphere 24 h after tMCAo by 4.61% (
0.39%), on the average (Fig. 2). However, 3 h delayed
treatment with (S)-8s (n = 19; dose: 2 mg/kg) was able to
reduce tMCAo-induced brain edema to 3.3% ( 0.38%),
a statistically significant difference (P < 0.05). These data
suggest that compounds similar to (S)-8s may have thera-
peutic utility in reducing brain edema after a transient
ischemic insult such as an embolic stroke.
The preliminary in vivo efficacy of (S)-8s in reducing the
ischemia-induced brain edema was evaluated in the rat
tMCAo model.16 Vehicle-treated animals (n = 21) typi-

1144
S.-M. Yang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1140–1145
Table 3. PK,a protein binding, and in vitro microsomal stability of selected compounds
AUCb (lg h/mL)
Vssb (L/kg)
CLb (mL/min/kg)
HLM/RLMc (t1/2, min)
PBc (%)
b
b
t1/2 (h)
Compound
Cmax (lM)
(S)-8b
(S)-8l
2.68
0.62
0.86
3.7
0.16
0.6
0.2
6.0
0.25
0.13
0.13
0.67
0.49
2.89
0.99
0.66
35.0
66.9
65.4
12.8
49/<9
<9/<9
84
99.7
74
(S)-8s
(S)-8ee
>2 h/>2 h
> 2 h/10
58
a Mean value of four animals (rats) at 0.5 mg/kg iv dose.
b Cmax, plasma concentration at t = 5 min; t1/2, apparent elimination half-life; AUC, area under curve; Vss, volume of distribution at steady state; CL,
clearance level.
c HLM, human liver microsome; RLM, rat liver microsome; PB, protein binding.
In conclusion, a new series of a-amino-b-N-biaryl ether
sulfonamide hydroxamates as potent gelatinase inhibi-
tors has been described. These compounds exhibited
low single-digit nanomolar activities against both
MMP-2 and MMP-9 and spared MMP-1. Particularly,
the analogs bearing an a-cyclic amino group showed
good water solubility, low protein binding, and an im-
proved PK profile (ex. (S)-8ee). (S)-8s reduced ische-
mia-induced brain edema in the rat tMCAo model,
also demonstrating a potential utility of these analogs
for the treatment of brain injury such as an embolic
stroke.
Acknowledgments
Many helpful discussions and suggestions from Dr. Paul
Jackson are gratefully acknowledged. The authors also
thank the Chem/Bio Support (CBS) Group for ADME
tests and the reviewers for the great comments.
O
O
O
O
O
O
References and notes
TrO
S
S
N
H
N
Me
N
HO
Me
N
1. Recent reviews, see: (a) Fingleton, B. Curr. Pharm. Des.
2007, 13, 333; (b) Fingleton, B. Exp. Opin. Ther. Targets
2003, 7, 385; (c) Vihinen, P.; Ala-aho, R.; Ka¨ha¨ri, V.-M.
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Neurosci. 2001, 2, 502.
N
a
O
O
O
O
(S)-14
(S)-13
CF3
CF3
b
O
O
O
O
O
O
2. (a) Clarke, A. W.; Krekoski, C. A.; Bou, S.-S.; Chapman,
K. R.; Edwards, D. R. Neurosci. Lett. 1997, 238, 53; (b)
TrO
S
HO
S
N
N
Me
N
N
Me
R
N
c
R
N
O
´
´
Joan Montaner, J.; Alvarez-Sabın, J.; Molina, C.; Angles,
A.; Abilleira, S.; Arenillas, J.; Gonzalez, M. A.; Monas-
´
O
terio, J. Stroke 2001, 32, 1759; (c) Romanic, A. M.; White,
R. F.; Arleth, A. J.; Ohlstein, E. H.; Barone, F. C. Stroke
1998, 29, 1020.
O
O
(S)-15
(S)-16
CF3
CF3
3. Asahi, M.; Wang, X.; Mori, T.; Sumii, T.; Jung, J. C.;
Moskowitz, M. A.; Fini, M. E.; Lo, E. H. J. Neurosci.
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Scheme 2. Reagents and conditions: (a) TrONH2, EDC, HOBt,
DMAP, rt, 24 h, 73%; (b) MeOTs or i-BuI, Cs2CO3, MeCN/DMF,
rt, 75–79%; (c) TFA, Et2O, rt, 65% ((S)-16a, R = Me), 75% ((S)-16b,
R = i-Bu).
5. Kim, S.-H.; Pudzianowski, A. T.; Leavitt, K. J.; Barbosa,
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8. a-Amino-b-sulfone hydroxamates as potent MMP-13
inhibitors have been reported recently, see: (a) Becker,
D. P.; Barta, T. E.; Bedell, L.; DeCrescenzo, G.; Freskos,
J.; Getman, D. P.; Hockerman, S. L.; Li, M.; Mehta, P.;
Mischke, B.; Munie, G. E.; Swearingen, C.; Villamil, C. I.
Bioorg. Med. Chem. Lett. 2001, 11, 2719; (b) Becker, D. P.;
DeCrescenzo, G.; Freskos, J.; Getman, D. P.; Hockerman,
6.00
n= 21
n= 19
5.00
4.00
3.00
2.00
1.00
0.00
-1.00
P < 0.05
Stroke + (S)-8s
(2 mg/kg)
Normal
Stroke + Vehicle
Figure 2. Brain edema in (S)-8s-treated animals (n = 19; dose: 2 mg/
kg).

S.-M. Yang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1140–1145
1145
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16. Focal cerebral ischemia of male Sprague–Dawley rats was
induced in the right hemisphere by occlusion of the middle
cerebral artery for 2 h, at which point the filament was
removed to allow for brain reperfusion. (S)-8s was
administered to the test animals 3 h post-filament insertion
via an intravenous bolus delivering 2.0 mg/kg drug solu-
tion combined with minipump implantation, which deliv-
ered a continuous intravenous infusion of a 30 mg/mL
drug solution for the duration of the study. Control
animals also receiving tMCAo were administered an
equivalent amount of the vehicle solution (20%
PEG400 + 80% of 20% solutol in distilled H2O) both as
a bolus and through minipump infusion. Twenty-four
hours after onset of ischemia animals were euthanized and
the brain was quickly removed to evaluate water content
by the wet/dry method. The water content in two
hemispheres of the brain tissue was calculated as follows:
100 · [(wet weight ꢀ dry weight)/wet weight] (%). The
percentage increase of the brain water content after
ischemia was calculated by the difference in water content
between the ischemic ipsilateral and non-ischemic contra-
lateral hemispheres. See: Yanamoto, H.; Nagata, I.;
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