Conversion of potent MMP inhibitors into selective TACE inhibitors

Article abstract of DOI:10.1016/j.bmcl.2005.10.078

Novel sultam hydroxamates with potent MMP activity were transformed into potent TACE inhibitors, lacking MMP activity. To accomplish this we relied on structural differences between the MMP and TACE S1′ pockets and the known advantageous fit of a 2-methyl

Full text of DOI:10.1016/j.bmcl.2005.10.078

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1028–1031
Conversion of potent MMP inhibitors into selective
TACE inhibitors
Robert J. Cherney,* Bryan W. King, John L. Gilmore, Rui-Qin Liu,
Maryanne B. Covington, James J.-W. Duan and Carl P. Decicco
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
Received 27 September 2005; revised 21 October 2005; accepted 24 October 2005
Available online 8 November 2005
Abstract—Novel sultam hydroxamates with potent MMP activity were transformed into potent TACE inhibitors, lacking MMP
activity. To accomplish this we relied on structural differences between the MMP and TACE S10 pockets and the known advanta-
geous fit of a 2-methyl-4-quinolinylmethoxyphenyl group into this region. From this approach, compound 7d was identified as a
potent TACE inhibitor (IC50 = 3.7 nM) that lacked MMP-1, -2, -9, and -13 activity.
Ó 2005 Elsevier Ltd. All rights reserved.
Several recently approved biologics have revolutionized
the treatment of autoimmune/inflammatory conditions,
including rheumatoid arthritis (RA) and Crohnꢀs
disease.1 These agents work by sequestering tumor
necrosis factor-a (TNF-a), which is an inflammatory
cytokine overproduced in these diseases. There is a great
deal of interest in finding a bioavailable small molecule
that can mimic these marketed biologics.2 We have pur-
sued the inhibition of TNF-a converting enzyme (TACE
or ADAM-17) as a means of TNF-a suppression.3,4
TACE is the protease responsible for processing the
membrane bound, pro-TNF-a (26 kDa) into the
17 kDa free form.5 As a member of the ADAM (a disin-
tegrin and metalloproteinase) family, TACE is con-
tained within the metzincin superfamily, which also
includes the matrix metalloproteinases (MMPs).6 Initial-
ly, it was shown that MMP inhibitors could prevent the
release of TNF-a from cells through their interaction
with TACE.5 Hence, many groups have used MMP
inhibitors as a starting point in the design of TACE
inhibitors.3 Recently, we described a novel set of sultam
hydroxamates (e.g., see compound 1, Fig. 1) as MMP
inhibitors that lacked TACE activity.7 In this communi-
cation, we describe our efforts to convert these
broad-spectrum MMP inhibitors into selective TACE
inhibitors, which lack MMP activity (see Fig. 1).
Figure 1. Design plan: from MMP inhibitor to TACE inhibitor.
As shown in Scheme 1, the synthesis of the sultam
hydroxamates follows that previously reported.7 For
example, the nitrogen of a five- or six-membered race-
mic sultam 3 (n = 1 or 2) was substituted via alkylation
or copper-promoted arylation8 to furnish 4. Subsequent
hydrogenolysis gave phenol 5, which was substituted
via an alkylation or Mitsunobu reaction to give 6.
Treatment of 6 with a basic hydroxylamine solution
afforded the target hydroxamates 7a–d.
Keywords: TACE inhibitor; ADAM-17 inhibitor.
*
As shown in Scheme 2, the route was adapted to
produce the cyclic sulfamide 13. In this case, the nitro-
Corresponding author. Tel.: +1 609 252 3066; fax: +1 609 252
6601; e-mail: robert.cherney@bms.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.10.078

R. J. Cherney et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1028–1031
1029
Scheme 2. Reagents and conditions: (a) (i) chlorosulfonyl isocyanate,
t-BuOH, CH2Cl2; (ii) 8, Et3N, CH2Cl2, 53%; (b) DIAD, PPh3, CH2Cl2,
67%, (c) H2, Pd(OH)2, MeOH, 26%; (d) 4-(benzyloxy)benzene boronic
˚
acid, Cu(OAc)2, Et3N, 4 A MS, CH2Cl2, 20%; (e) H2, Pd(OH)2,
Scheme 1. Reagents and conditions: (a) 4-(benzyloxy)benzyl chloride,
K2CO3, Bu4NI, DMF, 44%; (b) 4-(benzyloxy)benzene boronic acid,
˚
Cu(OAc)2, Et3N, 4 A MS, CH2Cl2, 26%; (c) 1-(2-bromoethyl)-4-
MeOH; (f) 4-(chloromethyl)-2-methylquinoline, K2CO3 CH3CN, 33%;
(g) H2NOHÆHCl, NaOMe, MeOH, 22%.
(phenylmethoxy)benzene, NaH, THF/DMF; (d) H2, Pd/C, MeOH; (e)
4-(hydroxymethyl)-2-methylquinoline, DEAD, PPh3, THF, 65% (6a);
69% (6b); (f) 4-(chloromethyl)-2-methylquinoline, K2CO3, MeCN, D,
50%; (g) 1.6 M H2NOH, KOH, MeOH, 19–59%.
situated in a very linear section of the MMP S10 pocket.7
Counter to this was the TACE S10 pocket, which has a
pronounced curvature in about the same area. We were
also aware of certain quinolines that when properly
placed could fit into the curvature of the TACE pocket
while clashing with the linear MMP pocket.10 Hence,
our strategy was to attach the quinoline moiety to the
sultam template and probe the different levels of S10 un-
til we could obtain the proper fit. As shown in Table 1,
the previously described 1 displayed good affinity for
MMP-2, -9, and -13 while lacking affinity for TACE
(IC50 > 1000 nM).11 In compound 7a, we introduced
the quinolinylmethoxy into the P10 region and this
resulted in a 1000-fold loss of binding across the MMPs,
while enhancing the affinity for TACE (TACE
IC50 = 900 nM). From here we set about probing S10
by deleting a methylene from 7a to give compound 7b.
Compound 7b appeared to have the proper fit of the
quinoline as the TACE affinity increased 150-fold over
compound 7a, while maintaining selectivity over the
MMPs. In order to secure this placement, compound
7c was synthesized to extend the quinoline moiety
further into S10, however it lost substantial TACE activ-
ity as compared to 7b. In an effort to optimize 7b, the
six-membered sultam 7d was synthesized and it proved
to be slightly more potent (TACE IC50 = 3.7 nM) than
7b. Additionally, a nitrogen was inserted into the sultam
ring to afford compound 13, but this proved to be detri-
mental as 13 was less active (TACE IC50 = 8.3 nM) than
7b. Removal of all the ring nitrogens gave cyclic sulfone
gen of N-benzyl serine 8 was substituted to afford
compound 9 through the action of N-tert-butoxy-
carbonylsulfamoyl chloride. Compound 9 was then cyc-
lized via an intramolecular Mitsunobu reaction to give
10. Hydrogenolysis gave 11, which was then arylated,
hydrogenated, and alkylated as before to afford 12.
Final conversion to the target hydroxamate 13 was
accomplished with a basic hydroxylamine solution.
As illustrated in Scheme 3, a 1,3-dipolar cycloaddition
was utilized to synthesize the cyclic sulfone 20. Using
the sequence of Achiwa et al.,9 silane 14 was condensed
with 4-benzyloxybenzaldehyde to give 15, which was
oxidized to 16. The cycloaddition was performed with
methyl acrylate to afford the regioisomers 17a and 17b.
Oxone oxidation of the mixture (17a and 17b) followed
by chromatographic separation gave the desired sulfone
18. Subsequent hydrogenation of 18 provided com-
pound 19. The phenol was substituted via a Mitsunobu
reaction and was then converted to the target hydroxa-
mate 20 as a racemic mixture of diastereomers.
As described in the introduction, it was our desire to
convert the non-selective MMP inhibitor 1 into a selec-
tive TACE inhibitor (see Fig. 1). From prior X-ray crys-
tal structures, we knew the biaryl of sultam 1 was

1030
R. J. Cherney et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1028–1031
20 as a racemic mixture of diastereomers. Compound 20
did show promise as it displayed 6-fold more affinity for
TACE when compared to the methylene linked com-
pound 7a.
In conclusion, we have successfully converted broad-
spectrum, sultam-based MMP inhibitors into potent
and selective TACE inhibitors. To accomplish this, we
altered the length our inhibitor in P10 by varying the dis-
tance between the known quinolinylmethoxyphenyl
moiety and the sultam core. Proper placement of this
moiety was achieved by direct attachment to the sultam
core, which resulted in the desired activity and selectivity
for TACE.
Acknowledgments
The authors thank Ruowei Mo and Dayton T.
Meyer for substantial quantities of the sultam 3.
We acknowledge John V. Giannaras and Paul
Strzemienski for Ki and IC50 determinations. We also
thank Dr. Percy H. Carter for a critical review of the
manuscript.
References and notes
1. (a) Haraoui, B. J. Rheumatol. Suppl. 2005, 32, 3; (b)
Keating, G. M.; Perry, C. M. BioDrugs 2002, 16, 111; (c)
Nanda, S.; Bathon, J. M. Expert Opin. Pharmacother.
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2295.
Scheme 3. Reagents and conditions: (a) n-BuLi, 4-benzloxybenzalde-
hyde, THF, 99%; (b) m-CPBA, CH2Cl2, ꢀ40 °C; (c) methyl acrylate,
HMPA, 100 °C, 20% (from 15); (d) oxone, MeOH, H2O; (e) H2,
Pd(OH)2, MeOH, 17%; (f) 4-(hydroxymethyl)-2-methylquinoline,
DEAD, PPh3, THF, 43%; (g) H2NOHÆHCl, NaOMe, MeOH, 28%.
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Levin, J. I. Annu. Rep. Med. Chem. 2003, 38, 153.
4. For an ADAM review, see: Moss, M. L.; White, J. M.;
Lambert, M. H.; Andrews, R. C. Drug Discovery Today
2001, 6, 417.
Table 1. In vitro evaluation
Compound
X
W
n
m
TACEa IC50 (nM)
Kia (nM)
MMP-9
46.7
>2128
MMP-1
MMP-2
MMP-13
1
—
N
—
—
l
—
1
>1000
900
>4949
>4949
>4949
>4949
>4949
>4949
>4949
3.8
>3333
>3333
>3333
>3333
>3333
>3333
55
>5025
>5025
>5025
>5025
>5025
>5025
7a
7b
7c
7d
13
20
CH2
CH2
CH2
CH2
NH
CH2
N
1
1
2
1
1
0
5.9
480
3.7
8.3
150
>2128
>2128
>2128
>2128
>2128
N
2
N
0
N
CH
0
1
a Values are an average from three determinations.

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