Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition

Article abstract of DOI:10.1016/j.bmcl.2011.09.036

Design, synthesis and structure-activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activit

Full text of DOI:10.1016/j.bmcl.2011.09.036

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6800–6803
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Continued exploration of biphenylsulfonamide scaffold as a platform
for aggrecanase-1 inhibition
Yonghan Hu a, Li Xing a, , Jennifer R. Thomason a, Jason Xiang a, Manus Ipek a, Satenig Guler b, Huanqiu Li c,
⇑
Joshua Sabatini a, Priya Chockalingam d, Erica Reifenberg e, Richard Sheldon d, Elisabeth A. Morris d,
Katy E. Georgiadis d, Steve Tam a
a Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 200 CambridgePark Drive, Cambridge, MA 02140, United States
b Astra Zeneca Research Center, 35 Gatehouse, Drive, Waltham, MA 02451, United States
c Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, United States
d Inflammation & Immunology, Pfizer Global Research and Development, 200 CambridgePark Drive, Cambridge, MA 02140, United States
e Echelon Biosciences, 675 Arapeen Drive, Suite 302, Salt Lake City, UT 84108, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2011
Revised 8 September 2011
Accepted 12 September 2011
Available online 18 September 2011
Design, synthesis and structure–activity relationship of a series of biphenylsulfonamido-3-methylbuta-
noic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition,
these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound
48 produced 87% inhibition of proteoglycan degradation at 10
lg/mL. Good pharmacokinetic properties
were demonstrated by 46 with a half-life of 6 h and bioavailability of 23%.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aggrecanase-1
MMP-13
Osteoarthritis
Biphenylsulfonamide
Osteoarthritis (OA) is a progressively debilitating disease affect-
ing approximately 40 million people in the United States. The ail-
ment is characterized by the destruction of articular cartilage
accompanied with chronic joint pain. In a normal articular joint
aggrecan and type II collagen molecules, the two main constituents
of the cartilaginous extracellular matrix responsible for the
mechanical operations of the cartilage, cooperatively maintain
the cartilage integrity and function. In osteoarthritic patients, the
two molecules are predominantly degraded through proteolytic
cleavage, by aggrecanases and matrix metalloproteinases (MMPs)
respectively, leading eventually to breakdown of the cartilage.
Currently there is no existing therapy to halt and/or reverse the
progression of this disease.
Aggrecanase-1 (Agg-1) is a member of ADAMTS (a disintegrin
and metalloproteinase with thrombospondin motifs) family of
zinc containing metalloproteinases. Along with Aggrecanase-2
(Agg-2), it is responsible for the cleavage of aggrecan IGD (inter-
globular domain) at the Glu373-Ala374 peptide bond. During the
early stages of osteoarthritis, and then through the disease states,
the loss of GAG-rich aggrecan fragments increases by progressive
proteolysis attributed to the ‘aggrecanase’ activity.1 Eventually
the cartilage is eroded and replacement joint surgery is usually re-
quired. Inhibition of aggrecanase-1 could impart overall cartilage
protection and offer a potential therapy that hamper the progres-
sion of OA.
While MMP inhibitors have been widely investigated by acade-
mia and pharmaceutical industry since the early 1990s,2,3 studies
on aggrecanase inhibition started to emerge more recently.4–9 In
an effort to find novel therapy for the treatment of osteoarthritis,
we have disclosed a series of potent and selective biphenylsulfona-
mide carboxylates as MMP-13 inhibitors.3 These MMP-13 inhibi-
tors all contain an animo acid as Zinc chelator, a biphenyl
backbone, and a benzofuran moiety in the deep end of the S10
pocket. Their high MW (ꢀ500) and ClogP (ꢀ6) present a challenge
for lead optimization (1 and 2). MMP inhibitors of biphenylsulf-
onamide carboxylic acid scaffold have been explored previously,
but mostly without further extension from the para-position of
the biphenyl moiety.6 Recent investigation revealed that a potent
MMP-13 inhibitor 2a (MMP-13 IC50: 0.004
aggrecanase-1 inhibitory activity (Agg-1 IC50: 0.7
l
M) also gave very good
l
M).8 We have
previously reported the preliminary results on Agg-1 inhibition
based on our initial discovery of MMP-13 inhibitors.8 In this Letter,
we describe our continued effort on modifying the biphenyl back-
bone and the SAR exploration of a variety of substituents beyond
the biphenyl P10 group of the Agg-1 inhibitors (3).
⇑
Corresponding author.
E-mail address: li.xing@pfizer.com (L. Xing).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.036

Y. Hu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6800–6803
6801
Table 1
R1
O
Agg-1 activities of B ring substitution
OO
NH
O
S
O
R
NH
HO
HO
OO S
O
O
NH
HO
1
R1
O
Compound
R
Agg-1 IC50 (lM)
O
O S
O
NH
3a
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
H
m-OH
3
9
2.1
8.4
m-CH2OH
2
m-C(O)NH2
m-NHC(O)Me
m-CH2NH2
m-CH2NHC(O)Me
m-CN
ꢀ20
1
2a
, R = H, Agg-1 IC50: 0.7 µM
7.2
>200
40
4.6
O
R
OO
S
A
B
p-OH
NH
p-CH2OH
15
HO
p-NHC(O)Me
p-OC(O)NHMe
p-OC(O)NH2
p-CH2NHC(O)Me
p-CH2N(Me)C(O)Me
p-CH2NHC(O)Ph
ꢀ100
ꢀ50
4.1
0.42
>200
ꢀ100
3
3a, R = H, Agg-1 IC50: 3 µM
Compound 3a employing an unsubstituted biphenyl displayed an
Agg-1 IC50 of 3 M. Previous investigation on the biphenyl back-
l
bone suggested that ortho-substitutions on the biphenyl backbone
significantly reduced the Agg-1 activity, possibly due to the disrup-
tion of the coplanar conformation of the biphenyl that is preferred
by Agg-1 binding.8 We then investigated the use of heterocycles
to replace the B ring of the biphenyl backbone (3). A variety of het-
eroaromatics were employed, with an attempt to explore polar
interaction with the backbone of the Agg-1 enzyme without dis-
rupting the binding conformation. These included pyridines, furan,
tetrazole, pyrimidine-2,4-dione, and pyridin-2-ones (4–12, Fig. 1).
All these modifications resulted in loss of Agg-1 activity (IC50
>10 lM) compared to the unsubstituted biphenyl compound (3a).
SAR on the meta- and para-positions of the biphenyl B ring (3)
was explored and the results are listed in Table 1. We selected
functional groups that contain hydrogen bond donor and/or accep-
tors, including hydroxyls (13, 14, 20 and 21), amides (15–18, 22,
and 25) and carbamates (23 and 24), again searching to form favor-
able interactions with the backbone of residues Phe357 and His361
and Val390 in the vicinity. While most functional groups resulted
in unchanged or reduced Agg-1 activity (14–24, 26), compound
25 showed a seven-fold improvement of activity compared to com-
pound 3.
Figure 2. Docking model of compound 25 (gold) in Agg-1.Zn2+ atom is coordinated
by the three histidines of Agg-1 and the carboxylate of 25. Ligand–protein H-bonds
are represented by red dash lines.
The X-ray crystal structure of inhibitor bound to Agg-1 protein
was previously reported by our laboratory.7b,10 Docking of com-
pound 25 into Agg-1 binding site revealed similar interactions to
the previously reported crystal complex of the congeneric com-
pound. The butanoic acid forms chelating bond with Zn2+, and
the cylindrical biphenyl backbone binds in the S10 pocket. Fig. 2
elucidates the key interactions of compound 25 with Agg-1 en-
zyme. One of the sulfonamide oxygen was involved in H-bond with
the backbone amide of Leu330 and Gly331. The para-amide NH of
the biphenyl backbone forms H-bond with His389 and its carbonyl
group is H-bonded to Ala396. The N-methylated analog 26 showed
complete loss of activity, corroborating the importance of the H-
bond interaction with His389.
As elucidated by the Agg-1 structure, Phe357 is in the vicinity of
the para-amido functionality of compound 25, which presents a
potential for p–p stacking. Direct replacement of the methyl group
in compound 23 with a phenyl group (27) resulted in loss of activ-
ity. Based on molecular modeling it is suggested that this phenyl
O
OO S
R
NH
HO
R:
N
N
N
N
O
O
N
4
5
6
7
8
O
NH
N
N
N
NH
O
O
HN
N
H
NH
group extends beyond Phe357 and hence the p–p stacking interac-
tion is not effectively engaged. Other linkages between a phenyl
group and the biphenyl P10 ligand were explored (Table 2). A
two-atom linker appears to position the terminal phenyl in the
9
10
11
12
Figure 1. Heterocyclic replacement of B ring resulted in loss of Agg-1 activity.

6802
Y. Hu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6800–6803
Table 2
Table 3
Substitution on para-position of B ring
Modification on compound with an ether linkage: Agg-1 (IC50 in micromolar) and
MMP-13 (IC50 in namomolar) activities
O
O
OO S
OO S
R
O
NH
HO
R
NH
HO
#
R
Agg-1 IC50 (lM)
#
R
Agg- MMP-
#
R
Agg- MMP-
28
29
30
31
32
–OPh
–OCH2Ph
–OC(O)NHPh
–OC(O)NHCH2Ph
–OSO2Ph
13.2
5.5
5.6
1
13
1
13
IC50
IC50
IC50
IC50
(
lM)
(lM)
(lM)
(lM)
ꢀ25
8.2
29 –CH2Ph
5.5
0.0056 46
15
0.0046
O
33
>75
CN
34
35
36
1.4
0.8
1.0
0.0071 47
0.0014 48
0.0052 49
0.8
0.0001
0.0035
0.0001
CN
proximity of Phe357 as indicated by the moderate activities of
compounds 29 and 32. Replacement of the phenyl group with a
cyclohexyl group resulted in complete loss of activity (compound
33). Nevertheless, the free energy gain from plausible p–p stacking
was not enough to offset the H-bond interaction that is presented
0.31
1.4
CF3
CN
N
N
by compound 25 with the enzyme.
CF3
We then replaced the phenoxy of 28 with a number of benzyl-
oxy functionality (Table 3). Fused bicyclic rings were examined
(34–38) in addition to the substituted aryl rings. Most of the bicy-
clic analogs (34–37) showed improvement of Agg-1 activity com-
pared to 29, except for compound 38 where a N atom is adjacent
to the benzylic methylene group. In particular, compound 37
showed an Agg-1 IC50 of 0.5 lM. Based on the position and orien-
tation denoted by molecular modeling it is suggested that the ben-
zylic aryl ring of the fused system makes major contribution to the
37
0.5
0.0096 50
1.9
0.002
38
10.6
NT
NT
51
52
2.7
0.012
CF3
NO2
N
39
ꢀ30
0.54
0.0014
N
N
O
40
33
NT
53
0.76
0.0026
0.0027
N
p–p
interaction with Phe357.
OMe
Substituted and/or unsubstituted pyridines were examined
(39–44). Consistent with compound 38 pyridine N appeared to
have a negative effect on Agg-1 activity (39–41 cf. 29). When a
methyl (42) or trifluoromethyl (43, 44) group was added to the
pyridine ring, Agg-1 activity recovered a little bit from the corre-
sponding unsubstituted pyridine.
To further our SAR understanding a series of substituents were
examined on benzyl group, including ortho-, para-, and meta-sub-
stitutions (47, 48, 51–58). ortho-Substitution (45, 46) did not help
activity. para-Substitution (49, 50) improved agg-1 activity by
three-fold. meta-Substitution has a much more significant impact
on Agg-1 activity (47, 48), demonstrating a 20-fold improvement
of Agg-1 activity in trifluoromethyl substitution (48 vs 29). Further
SAR showed that an electron withdrawing group at the meta-posi-
tion of the phenyl ring improved agg-1 activity (47, 52, 53, 56, 57).
Substitution on the benzylic position with a methyl group (51) did
not help Agg-1 activity.
O
41
8.5
0.0011 54
0.0007 55
ꢀ22
OH
N
N
42
43
2.4
2.2
4.7
2.6
0.0022
0.0014
1.6
F
0.001
4.3
56
57
0.4
Cl
CF3
CF3
44
0.42
N
Br
45
9.1
24.7
58
3.7
4.0
OH
CF3
Table 4
Selectivity profile and cellular activity.
This group of compounds in general displayed high solubility
and low permeability. For example, at physiological pH (7.4) 46
#
Agg-1 IC50 MMP-13
Agg-2 IC50 % Inhibition of degradation of
(l
(
l
M) IC50 M) M) proteoglycan
(
l
and 47 showed solubility of >100 lg/mL and 53 lg/mL respec-
at 10
lg/mL
tively. Compound 46 is negligibly permeable in CACO-2 cells, while
47 exhibited a low permeability of 0.8 ꢁ 10ꢂ6 cm/s. Compounds
were further evaluated for their pharmacokinetic properties in
male Sprague Dawley rats. Compound 46 exhibited low clearance
of 1.07 mL/min/kg, respectfully long half-life of 6 h, and moderate
bioavailability of 23%. Similarly analog 47 demonstrated a half-life
of 7 h in vivo, suitable for b.i.d dosing regimen.
We have previously reported that compound 2a showed good
inhibition of proteoglycan inhibition in a cell-based interlukin-1
stimulated bovine cartilage explant assay.7a While its Agg-1 inhib-
2a 0.7
25 0.42
48 0.31
0.004
0.45
0.0035
3.7
89
73% at 200 20
2.38 87
published by Pratta1a and Little,1b aggrecan is degraded early, dur-
ing the first week of the culture (days 3–7), whereas the collagen is
not rapidly degraded until later in the culture period (days 8–14).
There is no significant involvement of MMPs during this early stage
of proteoglycan degradation. Therefore, the activity in this 3-day
assay is indicative of aggrecanase inhibition. Compounds 25 and
48 were measured against MMP-13, aggrecanase-2 activities and
inhibition of proteoglycan degredation (Table 4). These two
itory activity (0.7
(0.004 M, Table 4), the 3-day cartilage explants assay is a good
measurement of aggrecanase activity. According to early work
lM) is much weaker than its MMP-13 activity
l

Y. Hu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6800–6803
6803
.HCl
NH2
phenol intermediate. The benzyloxyl analogs (29, 33–58) were
synthesized through direct alkylation of the phenol with benzyl
halides (Scheme 2).
O
O
R1O
OO
S
Br
NH
R1O
In summary, we herein report the design, synthesis and
structure–activity relationship of Agg-1 inhibitors based on
biphenylsulfonamido-3-methylbutanoic acid scaffold. These
Agg-1 inhibitors also exhibit potent MMP-13 inhibitory activities.
Compound 48 with a trifluoromethyl substitution on the benzyl-
oxy group beyond biphenylsulfonamide yielded good Agg-1 inhibi-
tion and high activity when evaluated in cell-based cartilage
explant assay for the inhibition of proteoglycan degradation,
indicative of aggrecanase inhibition and aggrecan protection.
R1 = But, Me
59
60
R1 = But, Me
a
b
O
O
OO
OO
S
R
S
R
c
NH
NH
R1O
HO
Acknowledgments
The authors thank Dr. Eddine Saiah for critical suggestions; Dr.
Nelson Huang and Ms. Ning Pan for LC–MS and HRMS measure-
ments; Dr. Walter Massefski for NMR measurements.
61
4-8, 10-23, 25-32
d
References and notes
O
N
O
OO S
NH
N
N
N
c
N
N
OO S
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H
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9
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62
Scheme 1. Reagents and conditions: (a) RSO2Cl, DIEA, DCM, 3 h (93%); (b) RSnBu3,
Pd(PPh3)4, toluene, reflux, 12 h or boronic acid/ester, Pd(PPh3)4, K2CO3, DME/H2O,
80 °C, 12 h (59–85%); (c) TFA, DCM, 3 h when R = But; LiOH, MeOH/THF, 24 h when
R = Me (100%); (d) Bu3SnN3, ethylene glycol diethylether, reflux, 24 h (87%).
R = p-
hydroxylbenzene
24
a, b
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2005, 4, 251.
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2001, 44, 3347; (b) Yao, W.; Chao, M.; Wasserman, Z. R.; Liu, R.-Q.; Covington,
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O
O
R = p-
H
N S
O
R
hydroxylbenzene
tBuO
32
c, b
R = p-
hydroxylbenzene
29
33-58
d, b
Scheme 2. Reagents and conditions: (a) ClSO2NCO, DCM, 16 h (45%); (b) TFA, DCM,
3 h (100%); (c) PhSO2Cl, DMAP, DCM, 12 h (75%); (d) benzyl halide, K2CO3, DMF,
12 h (38–72%).
compounds showed better activity in MMP-13 assay, representing
a general trend of compounds of this class. Indeed, all compounds
exhibited more potent MMP-13 activities than Agg-1 as shown in
Table 3. Compound 48 showed similar activity to 2a in cartilage ex-
plants assay, while compound 25 has weaker activity, possibly due
to its poorer cartilage penetration.11
The synthesis of aggrecanase-1 inhibitors with a biphenylsulfo-
namido-3-methylbutanoic acid scaffold is shown in Schemes 1
and 2.
8. (a) Xiang, J. S.; Hu, Y.; Rush, T. S.; Thomason, J. R.; Ipek, M.; Sum, P.-E.; Abrous,
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Briefly, as shown in Scheme 1, direct sulfonylation of amino
ester 59 or Suzuki/Stille coupling of 60 gave compound 61, which
was hydrolysized to give the respective acid (4–8, 10–23, 25–32).
Tetrazole analog 9 was synthesized through cyclization using
nitrile intermediate 61 (R = CN). The carbamoyloxy analog 24
was synthesized from the reaction of phenol with chlorosulfonylis-
ocyanate. Compound 32 was synthesized by direct sulfonation of
11. Studies showed that compound 25 had poor cartilage penetration, Pfizer
internal communication.