MMP-13 selective alpha-sulfone hydroxamates: Identification of selective P1′ amides

Article abstract of DOI:10.1016/j.bmcl.2011.03.095

Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1′ substituents. We identify an amide which spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8.

Full text of DOI:10.1016/j.bmcl.2011.03.095

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2823–2825
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
MMP-13 selective alpha-sulfone hydroxamates: Identification of selective
P10 amides
Yvette M. Fobian a, John N. Freskos a, Thomas E. Barta b, , Louis J. Bedell b, Robert Heintz a, Darren J. Kassab a,
⇑
James R. Kiefer a, Brent V. Mischke a, John M. Molyneaux a, Patrick Mullins a, Grace E. Munie a,
Daniel P. Becker b
a Departments of Medicinal Chemistry and Pharmacology, Pfizer Research & Development, 700 Chesterfield Village Parkway, St. Louis, MO 63198, USA
b Departments of Medicinal Chemistry and Pharmacology, Pfizer Research & Development, 4901 Searle Parkway, Skokie, IL 60077, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we
report on a series of hydroxamic acids with a flexible amide P10 substituents. We identify an amide which
spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 February 2011
Revised 23 March 2011
Accepted 24 March 2011
Available online 1 April 2011
Keywords:
MMP
Matrix metalloproteinases
MMP-13
Arthritis inflammation
Hydroxamic acids
Matrix metalloproteinases (MMPs) are a family of about 27
zinc-dependent enzymes responsible for the turnover of collagen
in connective tissue. There are a variety of disease states where
degradation of collagen contributes to the pathology, specifically
in osteo- and rheumatoid arthritis; in tumor angiogenesis and
metastasis; and in post-MI cardiovascular remodeling.1 In spite
of the promise that modulation of MMP activity offers, the delivery
of a suitable MMP inhibitor to pharmacy shelves has not been
realized. Clinical compounds often induce a dose-limiting joint-
stiffening referred to as musculoskeletal syndrome (MSS) thus
limiting their utility.
An alternative approach toward realizing efficacious MMP
inhibitors with reduced side effects is to focus on optimizing the
inhibition of the single MMP isozymes that should confer the most
therapeutic benefit, reducing the probability of off-target protease
inhibition. MMP-13 is an attractive isozyme to pursue; MMP-13
rapidly degrades type II collagen and is associated with pathology.
The isozyme is upregulated in osteoarthritic joints and in cancer.5
Structural studies show that MMP-13 differs from other MMP’s in
the depth of its S10 pocket, suggesting that lengthier inhibitors may
confer selectivity over other isozymes.
It has been hypothesized that inhibition by drug candidates of
MMP-1, a constitutive enzyme involved in the turnover of type II
collagen, contributes to MSS.2a Sparing MMP-1 may not be suffi-
cient. In our earlier research we saw that dosing with the MMP-1
sparing hydroxamate 1 (SC-276, Fig. 1) eventually led to joint stiff-
ening in animal models.2b MT1-MMP (MMP-14) may also play a
role in MSS, since it has been observed that MMP-14 knockout
mice suffer from joint lesions reminiscent of the changes in
MSS.3 The actual situation may be even more complex; MMP
inhibitors, even those that spare both MMP-1 and -14, may bind
to members of the structurally-related ADAMs family (A Disinte-
grin and Metalloprotease),4 leading to undesired joint effects.
O
O
O
HO
S
N
H
S
N
O
O
O
O
1
HO
S
SC-276
N
H
N
O
2
O
O
O
S
O
HO
N
H
O
O
N
N
3a
⇑
Corresponding author.
E-mail address: thomas_e_barta@yahoo.com (T.E. Barta).
Figure 1. MMP inhibitors. Compound 1 spares MMP-1; Compounds 2 and 3a are
MMP-13 selective.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.095

2824
Y. M. Fobian et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2823–2825
Table 1
O
O
O
MMP selectivity of studied compounds
S
O
+
HO
O
O
O
O
F
HO
a
O
S
N
4
(CH2)n
H
O
O
O
S
Y
O
O
O
O
O
O
d
a
#
n
Y
hMMP IC50 (nM)
5
O
O
O
b
c
-2
-8
-9
-13
S
O
O
81%
1
2
—
—
—
—
0.33
1.8
1.5
<1.0
8.0
O
OH
O
4000
>10k
>10k
6
e
O
O
i
O
S
O
N
3a
4
3
35
140
900
1100
NT
0.4
1.6
THPO
HO
f
O
N
H
O
OMe
NH
e
O
O
N
O
N
12a
550
1100
360
O
g
h
7
O
NH
O
S
f
O
N
H
O
12b
12c
3
3
1100
140
NT
1.6
h
O
NH
O
3b
OMe
OCF3
O
2200
0.66
O
S
O
O
NH
HO
OMe
16a
N
O
H
O
N
H
12d
12e
12f
3
3
3
940
650
450
700
NT
NT
NT
8.0
8.2
8.2
O
O
O
Scheme 1. Reagents and Conditions: (a) BnO(CH2)5OH (1.05 equiv), NaH 1.2
(equiv), 0 °C–rt, 4 h; (b) 5% Pd/C (wet), 80 psi, THF, 1.5 h; (c) 2.5% RuCl3, NaIO4
(3 equiv), CCl4, water; (d) triethylamine (6.0 eq), N-hydroxybenzotriazole (1.5 eq),
HN(Me)OMe (3.0 equiv), EDC (1.4), DMF, 16 h (e) trifluoroacetic acid, triturate; (f)
triethylamine (2.1 equiv), HOBT (3.0 equiv), THPONH2 (3.0 equiv), EDC (1.2 equiv),
DMF, 3.5 h 40 °C, rt 16 h; (g) 4-(MeO)PhMgBr (5 equiv), THF, 0 °C–rt overnight, then
NH4Cl; (h) 4 N HCl, dioxane, MeOH, triturate.
3100
1200
N
H
O
N
H
N
13
14
2
3
16
18
120
170
NT
0.9
0.2
O
N
930
O
O
S
O
O
O
O
O
15a
15b
15c
15d
3
3
3
3
10
100
31
960
23
1.7
0.3
0.2
3.3
HO
N
O
F
HN
O
N
O
H
a
53%
O
O
O
2.5
HN
O
O
S
O
O
O
N
O
O
11
6.7
49
180
380
H
HN
O
OCF3
OCF3
8
b
c
92%
O
O
O
S
O
O
270
O
O
N
HCl
O
NH2
O
O
9
15e
3
170
800
670
1.2
33%
N
O
S
O
O
O
N
H
16
17
4
4
1.8
2.6
67
500
NT
1.8
0.9
O
HN
N
OMe
d
e
10
O
O
6.6
a
O
O
f
For each compound, MMP-1 and MT1-MMP >5000, except for 1, where MT1-
O
HO
S
MMP = 8 nM.
N
H
O
12a
O
N
O
H
OMe
tive, ketones like 2 exhibited poor PK, so we endeavored to im-
prove their ADME properties, in part, though reduction of
molecular weight. Conceptually dissecting the piperidine ring in
compound 2 led to acyclic-chain analogs such as ketone 3a (Fig. 1).
The synthesis of ketone 3a and related ketones (e.g., 3b, Scheme
1) proceeded from aryl fluoride 4,8which was reacted with an ome-
ga benzyloxy 1-alkanol. The benzyl ether could be cleaved by
hydrogenation and the resulting alcohol oxidized to carboxylic acid
6. Acid 6 was converted using EDC coupling to a Weinreb amide9,
the t-butyl ester was cleaved with TFA affording acid 7, and this
acid was coupled with THPONH2. Excess aryl Grignard and subse-
quent treatment with HCl led to the final product, 3b. Similar
Scheme 2. Reagents and Conditions: (a) tert-butyl N-(3-hydroxypropyl)carbamate
(1.1 equiv), NaH (1.2 equiv), DMF, 0 °C, 18 h; (b) 4 N HCl/dioxane, 1 h; (c) DMF,
triethylamine (1.2 equiv), anisoyl chloride (1.2 equiv); (d) trifluoroacetic acid, 3 h,
concd at 50 °C; (e) Nmethylmorpholine (2.1 equiv), N-hydroxybenzotriazole
(1.2 equiv), THPONH2 (1.5 equiv), EDC (1.5 equiv), DMF,
dioxane, MeOH, 1 h, concd, triturate.
3 days; (f) 4 N HCl.
With this in mind, we previously reported a series of rigid pip-
eridino-ketones (compound 2, Fig. 1) with lengthier P10 subunits
and, with optimization, we achieved significant selectivity for
MMP-13 versus other MMP isoforms.6,7 Although potent and selec-

Y. M. Fobian et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2823–2825
2825
straightforward chemistry could be used to arrive at amides
including 16a.
(BA 1.5%), presumably due to in vivo amide hydrolysis, and that
was typical of the series. To address this issue, non-hydrolyzable
bioisosteric replacements for the amide linkage were sought, as re-
ported in the following Letter.
Isomeric amides such as 12a (Scheme 2) could be obtained
using, for example, tert-butyl N-(3-hydroxypropyl)carbamate,
which could be carried on to amine 9. Amine 9 was converted to
amide analogs 10, and on to final hydroxamic acids 12a.
We synthesized over 500 extended chain amides and ketones in
our MMP-13 program and the findings for selected analogs are
summarized in Table 1. Isonipecotate 2 demonstrates excellent
selectivity for MMP-13 versus the other MMP isoforms tested.
The direct open-chain analogs of 2, ketones 13, 14, and 3a, which
differ only in connecting chain length, are each more potent to-
ward MMP-13 than isonipecotate 2. Compounds 14 and 3a achieve
encouraging selectivity ratios for MMP-13 versus MMP-8, -9, -1,
and -14, but exhibit poor selectivity with respect to MMP-2.
We explored a variety of different linkers. Ether-linked com-
pounds including 17 lacked MMP-13/-2 selectivity. Amide analogs
made according to Scheme 1, such as 15a and 16, showed disap-
pointing selectivity, with 16 being essentially equipotent for
MMP-2, -8, and -13. N-Methylation, to alter the steric environ-
ment, did not improve the ratios, as can be seen from 15c and
15d. However, the isomeric benzamides (Scheme 2) look signifi-
cantly more attractive.
For example, compound 12b is potent for MMP-13, but unlike
its direct amide isomer, 15a, spares MMP-2 and -8. Conjugation
of the amide pi system into the aryl ring may diminish the confor-
mational mobility of these amides versus the amides of Scheme 1
(e.g., 12c vs 15c; 12a vs 15a) and this might account for the im-
proved selectivity of the latter series. Further exploration in the
series has shown the electronics of ring substitution did not have
a pronounced effect on potency/selectivity, although more hin-
dered analogs, such as 12d, saw a drop off in activity. Additionally,
saturated amides, including 12e and 12f exhibit reduced potency
and/or selectivity.
References and notes
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S., III; Hotchandani, R.; Du, X.; Geck, M.; Collins, E.; Xu, Z. B.; Skotnicki, J.; Levin, J.
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9. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
Benzamides like 12a and 12c became the focus of further study,
and, while we achieved meaningful levels of MMP-13 selectivity,
we did not find amides that had both high potency and acceptable
PK properties. Compound 12a had a half-life in rats of only 0.58 h