NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability

Article abstract of DOI:10.1021/jm020160g

The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et al. J. Am. Chem. Soc. 1997, 119, 5818-5827). While potent in vitro, these inhibitors exhibited no in vivo activity due, at least in part, to the poor pharmacokinetic properties of the alkylhydroxamate moiety. To circumvent this liability, NMR-based screening was implemented to identify alternative zinc-chelating groups. Using this technique, 1-naphthyl hydroxamate was found to bind tightly to the protein (K_D = 50 μM) and was identified as a candidate for incorporation into the lead series. On the basis of NMR-derived structural information, the naphthyl hydroxamate and biaryl fragments were linked together to yield inhibitors of this enzyme that exhibited improved bioavailability. These studies demonstrate that the NMR-based screening of fragments can be effectively applied to improve the physicochemical or pharmacokinetic profile of lead compounds.

Full text of DOI:10.1021/jm020160g

5628
J . Med. Chem. 2002, 45, 5628-5639
Articles
NMR-Ba sed Mod ifica tion of Ma tr ix Meta llop r otein a se In h ibitor s w ith Im p r oved
Bioa va ila bility
Philip J . Hajduk, Suzanne B. Shuker,† David G. Nettesheim, Richard Craig, David J . Augeri,‡
David Betebenner, Daniel H. Albert, Yan Guo, Robert P. Meadows, Lianhong Xu, Michael Michaelides,
Steven K. Davidsen, and Stephen W. Fesik*
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064
Received April 16, 2002
The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix metalloproteinase
stromelysin (MMP-3) has been previously described (Hajduk et al. J . Am. Chem. Soc. 1997,
119, 5818-5827). While potent in vitro, these inhibitors exhibited no in vivo activity due, at
least in part, to the poor pharmacokinetic properties of the alkylhydroxamate moiety. To
circumvent this liability, NMR-based screening was implemented to identify alternative zinc-
chelating groups. Using this technique, 1-naphthyl hydroxamate was found to bind tightly to
the protein (KD ) 50 µM) and was identified as a candidate for incorporation into the lead
series. On the basis of NMR-derived structural information, the naphthyl hydroxamate and
biaryl fragments were linked together to yield inhibitors of this enzyme that exhibited improved
bioavailability. These studies demonstrate that the NMR-based screening of fragments can be
effectively applied to improve the physicochemical or pharmacokinetic profile of lead compounds.
In tr od u ction
Another approach is to synthetically incorporate modi-
fications at or near the hydroxamate moiety in an
attempt to decrease the rate of hydrolysis or biliary
excretion in vivo. Both of these methods require exten-
sive synthetic efforts to produce the fully elaborated
compounds before it is known whether the modified
inhibitors will still bind to the enzyme or have the
desired properties.
Matrix metalloproteinases (MMPs) are a family of
zinc-dependent endoproteinases that are important in
tissue remodeling. When overexpressed or dysregulated,
these enzymes are associated with pathologies such as
arthritis and tumor metastases1,2 and have thus served
as drug targets to treat these diseases. Hydroxamic acid-
containing compounds potently inhibit MMPs and have
the potential to be useful drugs.3 In fact, several
hydroxamate-containing MMP inhibitors have been
clinically investigated, including marimistat,4 prinom-
astat,5 and CGS-27023A.6 However, many hydroxamate-
containing compounds exhibit rapid biliary excretion7
or are susceptible to hydrolysis to the corresponding
carboxylic acid in vivo,8,9 which may limit their useful-
ness as clinical agents.
Strategies have been developed to eliminate the
metabolic liability of hydroxamate-containing inhibitors.
One approach is to utilize replacements for the hydrox-
amic acid which still bind to the enzyme but that will
potentially exhibit improved pharmacokinetic proper-
ties. However, many of the known replacements (such
as thiol or phosphonate groups) have pharmacokinetic
(PK) liabilities of their own, while others (such as
carboxylic acids) typically result in compounds with
significantly reduced binding affinity for the enzyme.
We have previously reported on a fragment-based
approach for the optimization of lead compounds that
can be used to reduce the number of compounds that
need to be synthesized.10 Using this method, only those
fragments that bind to the protein are incorporated into
the lead series, reducing the synthetic effort and in-
creasing the chances that active compounds will be
produced. In addition, structural information on how the
fragments bind to the protein can help determine how
to incorporate these fragments into the final compound.
Here we describe the application of NMR-based frag-
ment optimization to biaryl-hydroxamate inhibitors of
stromelysin (MMP-3) that were previously discovered
using SAR by NMR.11 The initial inhibitors exhibited
potent (IC50 < 100 nM) in vitro activity,11 but lacked
oral bioavailability due to rapid hydrolysis of the hy-
droxamate group.12 On the basis of this series, potent
and orally bioavailable MMP inhibitors have been
successfully produced by modification of the hydroxam-
ate moiety.12,13 Here, we present an alternative ap-
proach wherein replacements for the acetohydroxamate
fragment of the biaryl-hydroxamate inhibitors were
identified using NMR-based screening. Incorporation of
an alternative fragment into the lead molecule produced
MMP inhibitors that exhibited significantly increased
bioavailability. These compounds represent novel MMP
* To whom correspondence should be addressed: Dr. Stephen W.
Fesik, Abbott Laboratories, D460, AP-10, 100 Abbott Park Road, Abbott
Park, IL 60064-3500. Phone: (847) 937-1201. Fax: (847) 938-2478.
E-mail: stephen.fesik@abbott.com.
† Current Address: School of Chemistry and Biochemistry, Georgia
Institute of Technology, Atlanta, GA 30332-0400.
‡ Current Address: Bristol-Myers Squibb Pharmaceutical Research
Institute, P.O. Box 5400, Princeton, NJ 08543-5400. Phone: (609) 818-
4943.
10.1021/jm020160g CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/20/2002

Matrix Metalloproteinase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5629
Ta ble 1. NMR Binding Data for Biaryl Compounds in the
Presence of Acetohydroxamate (1) and 1-Naphthylhydroxamate
(14)
(1, 13, and 14) exhibited any appreciable binding to
stromelysin. On the basis of the pattern of chemical shift
changes, all of the active compounds bound to the same
site on stromelysin as acetohydroxamate, indicating that
these compounds were indeed interacting with the
active site zinc (data not shown). 2-Thienylmercaptan
(4) and 1-naphthylhydroxamate (14) bound 100-fold
more tightly to stromelysin than acetohydroxamic acid
(1). This suggests that inhibitors containing these
moieties have the potential for even greater binding
affinity than those containing a simple alkyl hydroxamic
acid.
F igu r e 1. Summary of the SAR by NMR method as applied
to the design of biaryl-hydroxamate inhibitors of stromelysin.11
Since the incorporation of thiol groups (as in 4 and
5) may introduce another liability in the form of dimer
formation and covalent binding to plasma proteins,14
1-naphthylhydroxamate (14) was chosen as a replace-
ment fragment for acetohydroxamate. In addition to the
higher intrinsic affinity of 1-naphthylhydroxamate (KD
) 50 µM) vs acetohydroxamate (KD ) 17,000 µM), the
large naphthyl group could significantly change the
pharmacokinetic properties of the linked inhibitors (e.g.,
potentially hindering hydrolysis of the hydroxamate
group or potentiating biliary excretion), thereby increas-
ing the bioavailability of the series. Furthermore, on the
basis of binding experiments using NMR spectroscopy,
biaryls were able to bind with comparable affinity to
stromelysin in the presence of either acetohydroxamate
or 1-naphthylhydroxamate (see Table 1), indicating that
compounds which linked a biaryl to the naphthylhy-
droxamate could yield potent inhibitors of this enzyme.
Str u ctu r e of Str om elysin /1-Na p h th ylh yd r oxa m -
a te (14) Com p lex. To aid in the design of MMP
inhibitors containing a naphthylhydroxamate, an NOE-
based structure of the stromelysin/14 complex was
determined (Figure 3A). A total of 20 intermolecular
contacts between 1-naphthylhydroxamate and stromel-
ysin were derived from 13C-edited/12C-filtered NOESY
data sets. Hydrophobic contacts were observed between
the naphthyl moiety of 14 and Tyr155, Tyr168, Phe86,
His205, and Val163 of stromelysin. These data place the
naphthyl group in a hydrophobic pocket located in the
nonprime region of the active site (near the S1 subsite).
The experimentally determined orientation leaves the
S1′ subsite exposed and explains why the biaryl com-
pounds are able to bind in the presence of 14.
F igu r e 2. Compounds tested for their ability to chelate the
active site zinc in stromelysin and serve as replacement for
acetohydroxamic acid (1). NMR-derived KD values are given
after the compound number.
inhibitors that may be potentially useful for the treat-
ment of cancer.
Resu lts a n d Discu ssion
Id en tifica tion of Rep la cem en ts for th e Acetoh y-
d r oxa m ic Acid F r a gm en t. In our initial NMR work
on stromelysin,11 acetohydroxamic acid (1) was linked
to biphenyl-containing compounds (e.g., 2) to produce
MMP inhibitors with nanomolar potency (e.g, 3, see
Figure 1). However, all of the initial compounds lacked
oral bioavailability due to hydrolysis of the hydroxamic
acid.12 This is not unexpected for alkylhydroxamate-
containing compounds such as 3, where hydrolysis7,8
and rapid biliary excretion7 present major hurdles to
development. To identify alternative fragments to aceto-
hydroxamate that might have an improved pharmaco-
kinetic profile, compounds were tested for their ability
to bind to stromelysin in an NMR-based screen, in which
chemical shift changes were monitored in the 1H/15N
HSQC spectrum of stromelysin upon addition of test
compound. A diverse set of compounds was tested (see
Figure 2), which included thiols (e.g., 4 and 5), hydroxy-
ureas (e.g., 6), trifluoromethyl ketones (e.g., 8 and 9),
carboxylates (e.g., 11), and a variety of substituted
aromatic compounds. Of the tested compounds, only
thiol- (4 and 5) and hydroxamate-containing compounds
Design a n d Syn th esis of Lin k ed Com p ou n d s. On
the basis of the NMR-derived structural information of
the stromelysin/naphthylhydroxamate complex, com-
pounds in which the naphthylhydroxamate is linked to
the biaryl ligands were designed. A comparison of the
structures of stromelysin complexed to 1-naphthylhy-

5630 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
Hajduk et al.
F igu r e 3. NOE-based structures of (A) 1-naphthylhydroxamate (14, green carbon atoms) and (B) 2-[2-[(4′-cyano[1,1′-biphenyl]-
4-yl)oxy]ethoxy]-N-hydroxy-1-naphthalenecarboxamide (20, purple carbon atoms) bound to stromelysin. Residues of stromelysin
that make contact with the ligands are shown in orange. Also shown is the biaryl portion of 3 (cyan carbon atoms). Linkers were
designed to attach the 2-position of 14 (adjacent to the hydroxamate) to the phenolic hydroxyl of the biaryl.
Sch em e 1a
a
Reagents: (a) NBS, benzoyl peroxide, CCl4, 4; (b) Cs2CO3, 4-OHPhPhCN, DMF; (c) 1. PhLi, -78 °C, THF; 2. CO2; (d) 1. (COCl)2,
DMF; 2. NH2OH‚HCl, Et3N.
Sch em e 2a
and five-atom linkers, respectively) were synthesized
according to Schemes 3 and 4.
Biologica l Activity a n d Or a l Bioa va ila bility of
Lin k ed Com p ou n d s. Table 2 depicts the structures
of the initial series of linked compounds that were
synthesized along with their corresponding in vitro IC50
values as measured in a stromelysin inhibition assay.
The best compound in this series (20) exhibited an IC50
of 340 nM, 6-fold weaker than the lead biarylhydrox-
amate 3 (IC50 ) 57 nM). There is a marked dependence
of the inhibitory potency on the linker length in this
series. Compounds with linkers shorter than three
atoms (e.g., 18) show a more than 10-fold loss in enzyme
inhibition compared to 20 (see Table 2). Compounds
with longer linkers (e.g., 21) also show a more than 10-
fold loss in potency.
To determine whether the naphthylhydroxamate-
containing inhibitors of stromelysin had improved phar-
macokinetic profiles relative to the original biaryl-
hydroxamate inhibitor 3, the compounds were tested for
oral bioavailability in rats. The naphthyl-biaryl-hydrox-
amate 20 exhibits a superior pharmacokinetic profile
than the biaryl hydroxamate 3, as shown in Figure 4.
a
Reagents: (a) 4-ClPhPhOH, Ph3P, DIAD; (b) 1. n-BuLi, -78
°C, THF; 2. CO2; (c) 1. (COCl)2, DMF; 2. NH2OH‚HCl, Et3N.
droxamate (14) and the biarylhydroxamate 3 suggested
that the 2-position of 14 was well situated for incorpo-
rating linkers to access the S1′ subsite (see Figure 3).
Based on the distance between the 2-position of 14 and
the phenolic ether of 3 (∼5 Å), simple methylene/ether
linkers of 3-5 heteroatoms were proposed.
Compounds in which the biaryloxy and 1-naphthyl-
hydroxamate fragments are linked with two and three
atoms were readily synthesized by the routes shown in
Schemes 1 and 2 to produce compounds 18 and 19,
respectively. Compounds 20 and 21 (containing four-

Matrix Metalloproteinase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5631
Sch em e 3a
a
Reagents: (a) K2CO3, DMF; (b) H2, 10% Pd/C, AcOH-THF; (c) 1. (COCl)2, DMF; 2. BnNHOH‚HCl, Et3N, 3. H2, 10% Pd/C, THF.
Sch em e 4a
F igu r e 4. Blood levels of 3 (open triangles) and 20 (filled
circles) after oral administration (30 mg/kg) in rats.
cal potency. To verify that the linked compounds were
binding to stromelysin as designed, an NOE-based
model of the stromelysin/20 complex was determined
(Figure 3B). The biaryl moiety of 20 exhibits NOE
contacts to Val163, Leu197, Val198, and Leu218. These
contacts are essentially identical to those observed
between stromelysin and the biaryl moiety of 3, indicat-
ing that the biaryl groups in these two compounds are
binding in very similar orientations. The ethylene linker
and the 3-position of the naphthyl ring shows NOEs to
Val163, consistent with a binding orientation very
similar to that observed for the untethered 1-naphth-
ylhydroxamate (14). In addition, upon the binding of 20
to stromleysin, significant chemical shift changes were
observed for Tyr155, Val163, Ala165, Ala167, Tyr168,
and Ala169 as compared to the stromelysin/3 complex.
These residues are located at or near the proposed
naphthyl binding site (see Figure 3). Thus, the linked
compound 20 binds to stromelysin as designed, with the
biaryl moiety binding to the S1′ subsite and the naph-
thyl moiety occupying the hydrophobic pocket located
in the nonprime region of the active site.
a
Reagents: (a) 1. Br(CH2)3OAc, DMF, K2CO3; 2. Ba(OH)2. (b)
1. MsCl, Et3N; 2. 4-CNPhPhOH, K2CO3; 3. H2, 10% Pd/C. (c) 1.
(COCl)2, DMF; 2. BnONH2‚HCl 3. H2, 10% Pd/carbon, THF.
Ta ble 2. Stromelysin Inhibition for Linked
Biphenyl-naphthyl-hydroxamate Compounds
Design a n d SAR of Secon d -Gen er a tion Na p h -
th yl-bia r yl-h yd r oxa m a tes. Although the naphthyl-
hydroxmate inhibitor 20 was bioavailable, the potency
of this compound was weaker than the initial lead
series. This was contrary to what was expected, since
1-naphthylhydroxamate (14) exhibited a higher intrinsic
affinity for stromelysin than acetohydroxamate (1). The
weaker inhibitory potency of the linked compounds is
likely due, at least in part, to suboptimal positioning of
the naphthyl and/or biaryl fragments for interaction
The oral bioavailability for 3 is virtually nonexistent,
while the linked naphthylhydroxamate 20 exhibits a
C
indicate that the naphthyl-biaryl-hydroxamate series of
compounds represent lead MMP inhibitors with mark-
edly improved bioavailability.
Va lid a tion of Bin d in g Mod e. NMR binding studies
indicated that, on the NMR time scale, 20 was in slow-
exchange with stromelysin, consistent with its biochemi-
max of 28 uM and a half-life of nearly 2 h.15 These data

5632 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
Hajduk et al.
Sch em e 5a
a
Reagents: (a) 44a : nBu3P, ADDP; for 44b; 1.MsCl, Et3N, 2. K2CO3, DMF; (b) 4-MeOPhB(OH)2, Pd(PPh3)4, CsF, DME; (c) 3-(CH2CN)-
PhB(OH)2, Pd(PPh3)4, CsF, DME; (d) mCPBA, CH2Cl2; (e) H2, 10% Pd/C, AcOH-THF; (f) 1. (COCl)2, DMF, 2. NH2OH‚HCl, Et3N.
Sch em e 6a
For example, with a linker length of four atoms,
replacement of the biphenol oxygen of 20 with a sulfone
(22) resulted in no change in potency. The naphthol
oxygen in the linker was also not important, as replace-
ment of the naphthol oxygen of 22 with a methylene
(23) resulted in compounds with similar IC50 values.
However, replacement of the sulfone of 23 with a
sulfonamide (24) resulted in more than a 20-fold loss
in inhibitory activity. Only a modest loss in potency (4-
fold) was observed when the sulfone of 23 was replaced
by a ketone (25). Substituions at the 3′- and 4′-positions
of the biaryl also significantly affected potency. For
example, 4′-methoxy (22) and 4′-chloro (26) substituents
yielded compounds with similar potency, while the 3′-
cyanomethyl substituent (27) yielded a nearly 10-fold
gain in potency. Interestingly, this SAR matches that
previously observed for the unlinked biaryl fragments,
in which the potency rank order was 3′-cyanomethyl >
4′-methoxy ∼ 4′-chloro substitutions. This suggests that
the sulfone-containing linkers (e.g., compounds 22, 26,
and 27) are positioning the biaryl moiety in a compa-
rable position to that of the unlinked fragment. For
linker lengths of three atoms, the sulfonamide (28) was
superior in potency to both the sulfone (29) and the
ketone (30), in direct contrast to the SAR observed for
the four-atom linkers. Thus, by modifying the linker and
biaryl substitution pattern, a 10-fold gain in potency was
achieved, yielding a naphthyl-hydroxamate inhibitor
(27, IC50 ) 62 nM) that is equipotent to the parent biaryl
hydroxamate (3, IC50 ) 57 nM).
a
Reagents: (a) 1. n-BuLi, -78 °C, THF; 2. CO2; (b) Cs2CO3,
BnBr, DMF, 60 °C; (c) pTsOH‚H2O, MeOH; (d) 1. 4-BrPhSH,
n-Bu3P, ADDP; 2. 4-MeOPhB(OH)2, (Ph3P)4Pd, CsF, DME; 3. H2,
10% Pd/C; 4. (COCl)2, DMF; 5. NH2OH‚HCl, Et3N.
with the enzyme. As linker lengths of three or four
atoms gave rise to the most potent compounds in the
initial series of naphthyl-biaryl-hydroxmate inhibitors
(see Table 2), a variety of three- and four-atom linkers
were explored that might be more suitable for the
relative positioning of the naphthyl and biaryl groups.
In addition, linkers were chosen that had the potential
to form a hydrogen bond with the backbone amide of
Ala199, as previously observed between this residue and
the phenolic oxygen of the biarylhydroxamate 3.11 Thus,
ethers, ketones, sulfones, and sulfonamides were all
proposed as linker elements that possess slightly dif-
ferent geometries and contain at least one hydrogen
bond acceptor atom. Compounds containing these link-
ers were synthesized by the routes shown in Schemes
5-9.
Con clu sion s
The NMR-based screening of fragments has proven
to be a valuable tool in the drug discovery process. NMR
can be used to identify fragments that bind to protein
targets to produce potent leads,11,16 or to guide the
modification of lead compounds through fragment op-
timization.10,17 The power of these fragment-based ap-
proaches lies in the fact that, out of the hundreds or
Table 3 depicts second-generation linked compounds
that were synthesized along with their corresponding
in vitro IC50 values. As can be seen from these data,
the inhibitory activity of the linked compounds is
significantly modulated not only by the length of the
linker, but also by the chemical nature of the linker.

Matrix Metalloproteinase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5633
Sch em e 7a
a
Reagents: (a) Ph3P, DEAD, THF; (b) t-BuLl, -78 °C, THF; (c) NaH, DMF, BnOCOCl; (d) TFA; (e) 1. (COCl)2, DMF; 2. NH2OH.HCl,
Et3N; 3, H2, 5% Pd/C, MeOH.
Sch em e 8a
Sch em e 9a
a
Reagents: (a) 4-(4-Cl-Ph)-PhSO2Me, n-BuLi, THF, -78 °C; (b)
LiOH‚H2O, 80 °C, 16 h; (c) 1. (COCl)2, DMF; 2. NH2OH‚HCl, Et3N.
a
Reagents: (a) J ones reagent, acetone; (b) 1. SOCl2, benzene;
activity. Instead, efforts were directed at linking the
naphthyl hydroxamates, which were shown to bind to
the protein. Only four compounds (18-21) were pre-
pared in order to examine the effects of the naphthyl-
hydroxamate on potency and PK, and a sub-micromolar
inhibitor that possessed improved oral bioavailability
was identified. The SAR developed around this series
of inhibitors indicates that the exact positioning of the
biaryl and naphthyl moieties is critical for optimizing
compound potency. Thus, further modification of the
linker is one potential route for improving the potency
of this series of MMP inhibitors.
2. CH2N2, Et2O; 3. PhCO2Ag; 4. LiOH, 2-propanol; (c) 1. SOCl2,
benzene; 2. 4-MeOPh-Ph, AlCl3; (d) (Ph3P)4Pd, Ph3P, piperidine
(e) 1. (COCl)2, DMF; 2. NH2OH.HCl, Et3N.
even thousands of synthetic possibilities that confront
any given problem, the NMR-based screen can direct
the chemistry to include only those fragments that have
demonstrated affinity for the target. In the present
example, the chemistry efforts were directed away from
proposed zinc chelators that did not exhibit any observ-
able affinity for stromelsyin and that would have most
likely resulted in compounds with significantly reduced

5634 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
Hajduk et al.
the assignments were known.11 The 1H and 13C chemical shifts
of the side chain resonances were assigned from 3D HCCH-
Ta ble 3. Stromelysin Inhibition for Second-Generation Linked
Biphenyl-naphthyl-hydroxamate Compounds
1
TOCSY and H/13C NOESY spectra. NOEs between the ligand
and the protein were obtained from 2D and 3D 12C-filtered,
13C-edited NOESY spectra using mixing times ranging from
80 to 150 ms.
Intermolecular distance restraints between stromelysin and
14 were derived from the 3D 12C-filtered, 13C-edited NOESY
spectra and were given a lower bound of 1.8 Å and an upper
bound of 5.0 Å. Distance restraints between the catalytic zinc
and the hydroxamate were employed as previously described.11
Structures were calculated using a genetic algorithm-based
protocol (EGADS).18 The coordinates of the protein and the
catalytic zinc were taken from the structure of stromelysin
complexed to 311 and were held constant. Repulsive van der
Waals and NOE energies were employed as described18 using
force constants of 50 kcal mol-1 Å-2. A total of 45 structures
were generated with Etotal < 25 kcal mol-1 (ENOE < 10 and EVDW
< 20 kcal mol-1 for all structures), with a calculated rmsd of
0.77 Å to the average structure. The lowest energy structure
(Etotal ) 20.7, ENOE ) 4.9, and EVDW ) 15.6 kcal mol-1) was
used for the linker design and is shown in Figure 3.
Intermolecular distance restraints between stromelysin and
20 were also derived from 3D 12C-filtered, 13C-edited NOESY
spectra. All of the proton resonances for the biaryl and
ethylene linker moieties of 20 could be assigned. However,
when complexed to stromelysin, only the H3 position of the
naphthyl moiety of 20 could be observed. All of the other proton
resonances of the naphthyl moiety (H4 and H5-8) were
broadened due to chemical exchange phenomena and could not
be analyzed. Intermolecular distance restraints between
stromelysin and 20 were given a lower bound of 1.8 Å and an
upper bound of 5.0 Å. As with 14, distance restraints between
the catalytic zinc and the hydroxamate were employed as
previously described, and the coordinates of the protein and
the catalytic zinc were taken from the structure of stromelysin
complexed to 311 and held constant. 20 was initially docked to
stromelysin and then energy minimized using the program
XPLOR.19 The X-PLOR Frepel function was used to simulate
van der Waals interactions with a force constant of 4.0 kcal
mol-1 and with atomic radii set to 0.8 times their CHARMM
values. Distance restraints were employed with a square well
potential (FNOE ) 50 kcal mol-1 Å-2). The resulting energy-
minimized structure exhibited no significant steric or NOE
violations.
Exp er im en ta l Meth od s
Detection of Liga n d Bin d in g. The catalytic domain of
stromelysin (residues 81-256) was generated as previously
described.11 The NMR samples were composed of uniformly
15N-labeled stromelysin in an H2O/D2O (9/1) Tris-buffered
solution (50 mM, pH ) 7.0) containing CaCl2 (20 mM) and
sodium azide (0.05%). Ligand binding was detected by acquir-
ing sensitivity-enhanced 15N HSQC spectra11 on 400 µL of 0.3
mM protein in the presence and absence of added compound.
Compounds were added as solutions in perdeuterated DMSO.
A Bruker sample changer was used on a Bruker AMX500
spectrometer. Compounds were initially tested at 25.0 mM
each, and binding was determined by monitoring changes in
the 15N HSQC spectrum. Dissociation constants were obtained
for selected compounds by monitoring the chemical shift
changes of the amide resonances as a function of ligand
concentration. Data were fit using a single binding site model.
A least squares grid search was performed by varying the
values of KD and the chemical shift of the fully saturated
protein.
Str u ctu r a l Stu d ies. The NMR samples were composed of
uniformly 15N- or 15N/13C-labeled stromelysin (0.6 mM) and 1.0
mM 14 or 0.6 mM 20 in a D2O or H2O/D2O (9/1) Tris-buffered
solution (50 mM, pH ) 7.0) containing CaCl2 (20 mM) and
sodium azide (0.05%). All NMR spectra were recorded at 25
and 32 °C on Bruker AMX500, AMX600, or DMX500 NMR
spectrometers. In all NMR experiments, pulsed field gradients
were applied to afford the suppression of solvent signal and
spectral artifacts. Quadrature detection in the indirectly
detected dimensions was accomplished by using the States-
TPPI method. The data were processed and analyzed on Silicon
Graphics computers using in-house written software.
Deter m in a tion of Str om elysin In h ibition . IC50 values
were obtained for recombinant, truncated stromelysin as
previously described.11
Bioa va ila bility Mea su r em en ts. 3 and 20 were adminis-
tered po (30 mg/kg) in hydroxypropyl methyl cellulose vehicle
to a total of 4 rats each over two studies. Blood samples were
collected via tail vein at various intervals for 7 h after dosing
and deproteinated with 2 volumes of methanol containing 0.1%
acetic acid. Concentration of the compound in the methanol
extract was determined by bioassay using recombinant stromel-
ysin.
Ch em ica l Syn th esis. Gen er a l. 1H NMR spectra were
recorded on a GE QE300 spectrometer and chemical shifts are
reported in parts per million (δ, ppm) relative to tetrameth-
ylsilane as an internal standard. Melting points were deter-
mined using an Electrothermal digital melting point apparatus
and are uncorrected. Mass spectra were obtained on a Kratos
MS-50 instrument. Elemental analyses were performed by
Robertson Microlit Laboratories, Inc., of Madison, NJ . Unless
otherwise noted, all chemicals and reagents were obtained
commercially and used without purification. Reported chemical
yields are unoptimized and generally represent the result of
a single experiment.
Gen er a l Con d ition s for P r oced u r e A (Su zu k i cou -
p lin gs). A solution of the aryl bromide, 1.1 equiv of the
arylboronic acid, 3 equiv of cesium fluoride, and 0.05 equiv of
tetrakis(triphenylphosphine)palladium(0) in DME (75 mL) was
heated to reflux for 16 h, concentrated, and purified on silica
Chemical shift assignments for the stromelysin/14 and
stromelysin/20 complexes were obtained by comparison of
multidimensional 1H/13C double-resonance NMR experiments
with those obtained on the stromelysin/3 complex, for which

Matrix Metalloproteinase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5635
gel with 30% ethyl acetate/hexanes to provide the biaryl
intermediate.
filtered, and concentrated to an oil. The oil was purified on
silica gel with a gradient of 2% to 5% ethyl acetate/hexanes to
provide 11.8 g (87%) of 1-bromo-2-(2-methoxyethenyl)naph-
thalene. MS (DCI/NH3) m/e 263 (M + H)+.
A solution of 1-bromo-2-(2-methoxyethenyl)naphthalene
(11.8 g, 45.0 mmol) in 20% aqueous dioxane (150 mL) was
treated with p-toluenesulfonic acid (1.71 g, 9.00 mmol), heated
to reflux for 2 h, cooled to room temperature, and concentrated.
The residue was dissolved in diethyl ether, washed with
aqueous NaHCO3 and brine, dried (MgSO4), filtered, and
concentrated to an oil. The oil was purified on silica gel with
a gradient of 2% to 5% ethyl acetate/hexanes to provide 2.07
g (18%) 1-bromo-2-naphthaleneacetaldehyde MS (DCI/NH3)
m/e 249 (M + H)+.
A solution of 1-bromo-2-naphthaleneacetaldehyde (2.07 g,
8.35 mmol) in methyl alcohol (15 mL) was treated with sodium
borohydride (0.47 g, 12.5 mmol), stirred for 2 h, quenched by
addition to 1.0 M H3PO4, and concentrated. The residue was
dissolved in ethyl acetate, washed with water and brine, dried
(MgSO4), filtered, and concentrated to provide 1.52 g (73%) of
1-bromo-2-naphthalene ethanol (35). MS (DCI/NH3) m/e 252
(M + H)+.
A solution of 35 (1.51 g, 6.04 mmol), 4 chloro-4′-hydroxybi-
phenyl (1.35 g, 6.64 mmol), triphenylphosphine (2.37 g, 9.06
mmol), and diisobutylcarbodiimide (1.78 mL, 9.06 mmol) in
THF (10 mL) was stirred for 24 h, concentrated, and purified
on silica gel with 10% ethyl acetate/hexanes to provide 0.33 g
(28%) of 2-[2-[(4′-chloro[1,1′-biphenyl]-4-yl)oxy]ethyl]-1- bro-
monaphthalene (36). MS (DCI/NH3) m/e 456 (M + NH4)+.
A solution of 36 (0.33 g, 0.82 mmol) in THF (10 mL) at -78
°C was treated with n-butyllithium (0.37 mL, 0.92 mmol),
stirred cold for 15 min, treated with gaseous carbon dioxide,
stirred cold 15 min, quenched into 0.5 M aqueous HCl, and
extracted with ethyl acetate. The ethyl acetate was washed
with water and brine, dried (MgSO4), filtered, and concen-
trated to provide 0.33 g (89%) of 2-[2-[(4′-chloro[1,1′-biphenyl]-
4-yl)oxy]ethyl]-1-naphthoic acid 37. MS (DCI/NH3) m/e 420 (M
+ NH4).
The carboxylate intermediate 37 (0.32 g, 0.80 mmol) was
converted to the titled compound 19 (0.15 g, 46%) using
procedure B. MS (DCI/NH3) m/e 417 (M + H)+; 1H NMR
(DMSO-d6) δ 3.20 (t, 2H), 4.28 (t, 2H), 7.03 (d, 2H), 7.45 (d,
2H), 7.62 (m, 7H), 7.80 (d, 1H), 7.93 (m, 2H), 9.37 (s, 1H), 11.08
(s, 1H). Anal. Calcd for C25H20NO3Cl‚0.5 H2O: C, 70.34; H,
4.96; N, 3.28. Found: C, 70.48; H, 4.87; N, 3.29.
Gen er a l Con d ition s for P r oced u r e B (p r ep a r a tion of
N-h yd r oxy-1-n a p h th a len eca r boxa m id es). To a cooled (0
°C) solution of the 1-naphthalenecarboxylic acid intermediate
in dichloromethane (20 mL) was added 1.2 equiv of oxalyl
chloride and DMF (2 drops). The mixture was stirred cold for
20 min and then allowed to come to ambient temperature over
1 h. The solution was then added dropwise to a rapidly stirred
solution of 5 equiv of both hydroxylamine hydrochloride and
triethylamine in a mixture of THF:water (110 mL, 10:1). The
mixture was stirred for 2 h, reduced in volume under reduced
pressure, poured into aqueous H3PO4, and extracted with ethyl
acetate (3 × 35 mL). The combined organic layers were washed
with water (2 × 25 mL), brine (1 × 25 mL), dried (MgSO4),
and filtered, and the solvents were removed under reduced
pressure. The residue was crystallized from hot ethyl acetate
to provide the final N-hydroxy-1-naphthalenecarboxamide
product.
Syn th esis of 2-[2-[(4′-Cya n o[1,1′-bip h en yl]-4-yl)oxy]-
m eth yl]-N-h ydr oxy-1-n aph th alen ecar boxam ide (18,Scheme
1). A solution of 1-bromo-2-methylnaphthalene (31) (22.11 g,
0.10 mol), N-bromosuccinimide (19.57 g, 0.11 mol), and benzoyl
peroxide (2.42 g, 10 mmol) in carbon tetrachloride (85 mL) was
heated to reflux for 16 h, cooled to ambient temperature, and
filtered. The liquid was reduced in volume and filtered. The
solvents were removed under reduced pressure, and the
resulting oil was crystallized from hot diethyl ether/hexane.
The resulting solid was recrystallized from hot benzene/hexane
to provide 1-bromo-2-bromomethyl)naphthalene (32) (13.4 g,
45%). 1H NMR (DMSO-d6) δ 4.99 (s, 2H), 7.68 (m, 3H), 8.01
(m, 2H), 8.25 (d, J ) 9.8 Hz, 1H), MS (ESI) m/z 300 [M + H]+.
A mixture of 32 (2.0 g, 6.71 mmol), 4′-hydroxy[1,1′-biphenyl]-
4-carbonitrile (1.44 g, 7.38 mmol) and cesium carbonate (3.28
g, 10 mmol) in DMF (10 mL) was stirred under an atmosphere
of nitrogen for 16 h. The mixture was poured into cold aqueous
ammonium chloride, stirred for 0.5 h, and filtered. The residue
was crystallized from hot ethyl acetate to provide 4′-[(1-bromo-
2-naphthyl)methoxy][1,1′-biphenyl]-4-carbonitrile (33) (2.19 g,
79%). 1H NMR (DMSO-d6) δ, 5.46 (s, 2H), 7.20 (d, J ) 8.82
Hz, 2H), 7.67 (m, 1H), 7.75 (m, 4H), 7.86 (m, 4H), 8.03 (dd, J
) 3.68, 7.72 Hz, 2H), 8.28 (d, J ) 8.46, 1H), MS (ESI) m/z 415
[M + H]+.
To a solution of 33 (1.43 g, 3.47 mmol) in THF (30 mL) cooled
to -78 °C was slowly added phenyllithium (2.22 mL, 3.99
mmol). The mixture was stirred cold for 45 min, CO2 gas was
bubbled through for 5 min, and the mixture was allowed to
warm to 0 °C. The mixture was then quenched with 1 M
aqueous H3PO4 and extracted with ethyl acetate (3 × 35 mL).
The combined organic layers were washed with water (2 × 20
mL) and aquoues brine (1 × 20 mL), dried MgSO4, and filtered
and the sovents removed under reduced pressure. The residue
was precipitated from diethyl ether to provide 2-{[(4′-cyano-
[1,1′-biphenyl]-4-yl)oxy]methyl}-1-naphthoic acid (34) (0.99 g,
76%). 1H NMR (300 MHz, DMSO-d6) δ, 5.37 (s, 2H), 7.15 (d, J
) 8.82 Hz, 2H), 7.62 (m, 2H), 7.72 (m, 4H), 7.86 (m, 4H), 8.01
(m, 3H), MS (ESI) m/z 378 [M + H]-.
Syn th esis of 2-[2-[(4′-Cya n o[1,1′-bip h en yl]-4-yl)oxy]-
eth oxy]-N-h ydr oxy-1-n aph th alen ecar boxam ide (20,Scheme
3). To a solution of 4′-hydroxy-4-biphenylcarbonitrile (1.014
g, 5.19 mmol) in 10 mL of DMF was added potassium
carbonate (2.15 g, 15.6 mmol, 3 equiv) and acetic acid 2-bro-
moethyl ester (1.0 g). After 2 h at 50 °C, the reaction mixture
was cooled to room temperature, diluted with 50 mL of EtOAc,
washed with H2O (3 × 10 mL), dried (Na2SO4), filtered, and
concentrated to provide a white solid. The solid was dissolved
in 20 mL of MeOH, and 5 mL of H2O and potassium carbonate
(2.15 g, 15.6 mmol) were added. After 30 min, the MeOH was
evaporated and the crude reaction was taken up in EtOAc and
washed with H2O (10 mL × 3), dried (Na2SO4), filtered,
concentrated, and purified on silica gel to provide 0.967 g (78%)
of 2-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]ethanol. 1H NMR (300
MHz, CDCl3) δ 7.79-7.60 (m, 4H), 7.57-7.52 (m, 2H), 7.05-
7.01 (m, 2H), 4.15 (2H), 4.08-3.98 (m, 2H), 2.04 (t, 1H).
To a solution of 2-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]ethanol
(150 mg, 0.63 mmol) in 6 mL CH2Cl2 at 0 °C was added
triethylamine (127 mg, 1.26 mmol, 2 equiv) followed by
methanesulfonyl chloride (108 mg, 0.94 mmol, 1.5 equiv). After
stirring at ambient temperature for 4 h, the reaction mixture
was concentrated and purified on silica gel with 25% EtOAc/
hexanes to provide 185 mg (92%) of 4′-(2-hydroxyethoxy)[1,1′-
biphenyl]-4-carbonitrile methanesulfonate (39) as a white
solid. 1H NMR (CDCl3) δ 7.73-7.70 (m, 2H), 7.66-7.62 (m,
2H), 7.58-7.52 (m, 2H), 7.04-6.99 (m, 2H), 4.63-4.60 (m, 2H),
4.33-4.30 (m, 2H), 3.11 (s, 3H).
The carboxylate intermediate 34 (0.98 g, 2.6 mmol) was
converted to the titled compound 18 (0.45 g) using procedure
1
B. H NMR (DMSO-d6) δ, 5.29 (s, 2H), 7.17 (d, J ) 9.16 Hz,
2H), 7.61 (m, 2H), 7.70 (m, 4H), 7.85 (m, 4H), 8.01 (m, 2H),
9.37 (s, 1H), 11.14 (s, 1H), MS (ESI) m/z 393 [M + H]-. Anal.
Calcd for C25H18N2O3‚0.25H2O: C, 75.27; H, 4.67,:N, 7.02.
Found: C, 75.68; H, 4.68,:N, 6.62.
Syn th esis of 2-[2-[(4′-Ch lor o[1,1′-bip h en yl]-4-yl)oxy]-
eth yl]-N-h ydr oxy-1-n aph th alen ecar boxam ide (19, Scheme
2). A solution of (methoxymethyl)triphenyl phosphonium
chloride (32.0 g, 93.3 mmol) in THF (100 mL) at -78 °C was
treated with potasium tert-butoxide (9.90 g, 88.1 mmol), stirred
cold for 1 h, treated with a solution of 1-bromo-2-naphthalde-
hyde (12.1 g, 51.7 mmol) in THF (75 mL) over 15 min, stirred
for 16 h at room temperature, treated with aqueous am-
monium chloride (200 mL), and extracted with ethyl acetate.
The ethyl acetate was washed with brine, dried (MgSO4),

5636 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
Hajduk et al.
To a solution of benzyl 2-hydroxy-1-naphthalenecarboxylate
(38) (459 mg, 1.65 mmol) and mesylate 39 (475 mg, 1.5 mmol)
in 20 mL of DMF was added K2CO3 (623 mg, 4.5 mmol). The
reaction was allowed to stir at 50 °C for 14 h and then
partitioned between EtOAc and sat. NH4Cl, washed with brine,
dried (MgSO4), filtered, and concentrated to give benzyl 2-[2-
[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]ethoxy]-1-naphthoic acid (40)
which was used as is in the following experiment. In a separate
experiment the compound was purified via silica gel chroma-
tography eluting with 25% ethyl acetate/hexanes. 1H NMR
(CDCl3) δ 7.91 (d, 1H), 7.82-7.63 (m, 6H), 7.55-7.28 (m, 10H),
7.02-6.97 (m, 2H), 5.45 (s, 2H), 4.49 (dd, 2H), 4.26 (dd, 2H).
A solution of crude 40 (theory 1.5 mmol) in THF (30 mL) was
treated with 10% Pd on carbon (20 mg), and the gas in the
reaction vessel was evacuated twice and replaced with hydro-
gen. The reaction mixture was stirred overnight at rt and then
filtered. The filtrate was concentrated to give 294 mg (48%
yield) of 41, which was used as is in the following experiment.
Oxalyl chloride (0.54 mL, 1.08 mmol) was added dropwise over
15 min to a suspension of 41 (150 mg, 0.26 mmol) in CH2Cl2
(15 mL) and DMF (0.02 mL) resulting in a clear solution, which
was stirred at rt an additional 15 min and then concentrated
in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and
then treated with O-benzylhydroxylamine hydrochloride (117
mg, 0.73 mmol). The reaction mixture was stirred at rt for 15
min, washed with saturated aqueous NH4Cl, saturated aque-
ous NaHCO3, and brine, dried (MgSO4), filtered, and concen-
trated. The solid residue was washed with EtOAc, dissolved
in THF (10 mL), and treated with 10%Pd on carbon (10 mg),
and the gas in the reaction vessel was evacuated twice and
replaced with hydrogen. The reaction mixture was stirred
overnight at rt and then filtered. The filtrate was washed with
EtOAc and dried to give 44 mg (40% yield) of 20. mp ) 168-
washed with EtOAc and dried to give 138 mg (24% yield) of
2-[2-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyloxy]-N-hydroxy-1-
naphthalenecarboxylic acid (43).
The carboxylate intermediate 43 (0.14 g, 0.32 mmol) was
converted to the titled compound 21 (0.01 g, 17%) following
the procedure described for the conversion of 41 to 20. 1H NMR
(CDCl3), δ 8.2-7.75 (m, 3H), 7.70-7.25 (m, 9H), 7.05-6.95 (m,
2H), 4.45-4.35 (m,2H), 4.3-4.2 (m, 2H), 2.4-2.3 (m, 2H).
HRMS (FAB) C27H22N2O4 MH+ Calcd. 439.1658, found 439.1680.
Syn th esis of N-Hyd r oxy-2-[2-[(4′-m eth oxy[1,1′-bip h en -
yl]-4-yl)thio]ethoxy]-1-naphthalenecarboxamide (22,Scheme
5). A room-temperature solution of 1,1′-(azodicarbonyl)dipip-
eridine) (ADDP) (0.684 g, 2.7 mmol) in benzene (6 mL) was
treated with tributylphosphine (0.695 mL, 2.7 mmol) and a
solution of 44a (0.42 g, 1.80 mmol) in benzene (3 mL) and
stirred for 5 min, followed by addition of 38 (0.503 g, 1.81
mmol). The resulting mixture was diluted with 3 mL of
benzene, stirred for 45 min, and concentrated in vacuo. The
residue was purified on silica gel using 10% ethyl acetate in
hexanes to provide 0.62 g (70%) of 2-[2-(4-bromophenylsulfa-
nyl)ethoxy]naphthalene-1-carboxylic acid benzyl ester (45a ).
2-[2-(4-(4-methoxyphenyl)phenylsulfanyl)ethoxy]naphthalene-
1-carboxylic acid benzyl ester (45b) was prepared from 45a
using 4-methoxyphenylboronic acid in procedure A.
The title compound (22) was converted from 45b according
to the procedure described for the conversion of 45d to 26. MS
1
(DCI/NH3) m/e 478 (M + H)+; H NMR (300 MHz, DMSO-d6)
δ 4.87 (m, 2H), 4.46 (m, 2H), 3.80 (s, 3H), 7.41 (m, 2H), 7.56
(m, 4H), 7.78 (m, 3H), 7.98 (m, 5H), 9.20 (s, 1H), 11.02 (s, 1H).
Anal. Calcd for C26H23NO6S: C, 65.39; H, 4.85; N, 2.93.
Found: C, 65.09; H, 5.02; N, 2.72.
Syn th esis of N-Hyd r oxy-2-[3-[(4′-m eth oxy[1,1′-bip h en -
yl]-4-yl)su lfon yl]p r op yl]-1-n a p h th a len eca r boxa m id e (23,
Scheme 6). A mixture of 48a (2.96 g, 11.2 mmol) and 3,4-
dihydro-2H-pyran (2.04 mL, 22.4 mmol) in CH2Cl2 and was
stirred at 0 °C for 10 min and at room temperature for 40 min.
The reaction mixture was partitioned between CH2Cl2 and
water, dried (Na2SO4), filtered, concentrated, and purified on
silica gel with 10% ethyl acetate/hexanes to provide 3.73 g
(95%) of 48b. MS (DCI) m/e 366, 368 (M + NH4)+.
48b was converted to 49a according to the procedure
described for the conversion of 36 to 37. MS (DCI) m/e 313 (M
- H)-, 337 (M + Na)+, 332 (M + NH4)+.
A solution of 49a (2.05 g, 6.53 mmol) in DMF (25 mL) was
treated with cesium carbonate (3.2 g, 9.8 mmol) and benzyl
bromide (1.16 mL, 9.75 mmol), stirred at 60 °C for 40 min,
partitioned between ethyl acetate and water, dried (Na2SO4),
filtered, concentrated, and purified on silica gel with 7% ethyl
acetate/hexanes to provide 2.0 g (76%) of 49b. MS (DCI) m/e
422 (M + NH4)+.
A solution of 49b (2.0 g, 4.95 mmol) in methanol was treated
with p-toluenesulfonic acid hydrate (84 mg, 0.44 mmol), stirred
at room temperature for 2 h, partitioned between ethyl acetate
and water, dried (Na2SO4), filtered, concentrated, and purified
on silica gel with 30% ethyl acetate/hexanes to provide 1.5 g
(95%) of 2-(3-hydroxypropyl)naphthalene-1-carboxylic acid
benzyl ester (49c). MS (DCI) m/e 321 (M + H)+, 338 (M +
NH4)+.
49c was reacted with 4-bromothiophenol using the standard
Mitsunubu conditions described for the preparation of 45a to
give phenylmethyl 2-[3-[(4-bromophenyl)thio]propyl]-1-naph-
thalenecarboxylate, which was then reacted with 4-methoxy-
benzene boronic acid under the described conditions in pro-
cedure A to give phenylmethyl 2-[3-[(4′-methoxy[1,1′-biphenyl]-
4-yl)thio]propyl]-1-naphthalenecarboxylate. This was converted
to 23 in the same fashion as the 46d was converted to 26. mp
105.4 °C decomposed; MS (APCI) m/e 585 (M + Cl)-, 568 (M
+ NH4)+; 1H NMR (DMSO-d6) δ 1.90-2.02 (m, 2H), 2.757-
2.806 (t, 2H, J ) 6.9 Hz), 3.819 (s, 3H), 7.058 (td, 2H, J ) 2.1,
8.7 Hz), 7.372-7.400 (d, 1H, J ) 8.4 Hz), 7.540-7.572 (2H),
7.704-7.758 (m, 3H), 7.880-7.908 (m, 6H), 9.226 (s, 1H),
10.968 (s, 1H). Anal. Calcd for C27H25NO5S‚0.5H2O, C, 66.92;
H, 5.40; N, 2.89. Found: C, 66.93; H, 5.37; N, 2.67.
1
171 °C (dec). H NMR (DMSO-d6) δ 9.18 (d, J ) 1.7 Hz, 1H),
7.96 (d, J ) 9.2 Hz, 1H), 7.87-7.83 (m, 5H), 7.75-7.70 (m,
3H), 7.55-7.49 (m, 3H), 4.43-7.38 (m, 1H), 7.16-7.13 (m, 2H),
4.54-4.51 (m, 2H), 7.40-7.38 (m, 2H); MS (APCI) m/e 425 (M
+ H)+. HRMS (FTMS) C26H21N2O4 [M + Na]+ Calcd 447.1315,
found 447.1310.
Syn th esis of 2-[2-[(4′-Cya n o[1,1′-bip h en yl]-4-yl)oxy]-
p r op yloxy]-N-h yd r oxy-1-n a p h th a len eca r boxa m id e (21,
Scheme 4). A solution of 38 (600 mg, 2.16 mmol) and 3-acetyl-
oxy-1-propyl bromide (469 mg, 2.59 mmol) in DMF (15 mL)
was treated with K2CO3 (894 mg, 6.47 mmol), stirred at 55 °C
for 3 h, and then cooled to room temperature and partitioned
between EtOAc and water. The organic extract was washed
with saturated aqueous NH4Cl and brine, dried (Na2SO4),
filtered, and concentrated. The crude product was dissolved
in MeOH saturated with Ba(OH)2‚8H2O (20 mL), and the
resulting suspension was stirred for 15 min at room temper-
ature and then partitioned between saturated aqueous
NH4Cl and EtOAc (2×). The combined organic extracts were
washed with brine, dried (MgSO4), filtered, concentrated, and
purified via silica gel chromatography to give 441 mg (61%
yield) of 2-(3-hydroxypropoxy)naphthalene-1-carboxylic acid
benzyl ester (42).
A solution of 42 (441 mg, 1.31 mmol), methylsulfonyl
chloride (0.122 mL, 1.57 mmol), and Et3N (0.219 mL, 1.57
mmol) in CH2Cl2 (15 mL) was stirred at 40 °C for 18 h and
then allowed to cool to room temperature and partitioned
between saturated aqueous NH4Cl and EtOAc. The organic
extract was washed with brine, dried (MgSO4), filtered, and
concentrated. The crude product was dissolved in DMF (15
mL), treated with 4-(4′-hydroxyphenyl)benzonitrile (307 mg,
1.57 mmol), K2CO3 (540 mg, 3.91 mmol), and stirred at 60 C
for 3 h. The reaction mixture was then allowed to cool to room
temperature and partitioned between water and EtOAc. The
organic extract was washed with brine, dried (MgSO4), filtered,
and concentrated. The crude product was dissolved in THF
(15 mL) treated with catalytic amount of 10% Pd/carbon (30
mg), and the atmosphere in the flask was evacuated and filled
with H2 (via a hydrogen balloon). The reaction was stirred
under H2 overnight, the catalyst was removed via filtration,
and the filtrate was concentrated. The residual solid was

Matrix Metalloproteinase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5637
Syn th esis of N-Hyd r oxy-2-[2-[[(4′-m eth oxy[1,1′-bip h en -
yl]-4-yl)su lfon yl]am in o]eth yl]-1-n aph th alen ecar boxam ide
(24, Scheme 7). The title compound was prepared following
the procedures for the preparation of 28, substituting 4-meth-
oxyphenyl boronic acid for 4-trifluomethoxyphenyl boronic acid
and 35 for 50. 1H NMR (CD3OD) δ 7.84 (d, 1H), 7.74-7.69 (m,
4H), 7.56-7.51 (m, 5H), 7.48-7.43 (m, 1H), 7.26 (d, 1H), 7.02
(d, 2H), 3.85 (s, 3H), 3.27-3.25 (m, 2H), 2.92 (t, 2H); HRMS
(FAB) C26H24N2O5S MH+ Calcd 477.1484, found 477.1479.
Syn th esis of N-Hyd r oxy-2-[4-(4′-m eth oxy[1,1′-bip h en -
yl]-4-yl)-4-oxobutyl]-1-n aph thalen ecar boxam ide (25,Scheme
8). A solution of 57 (1.4 g, 5.18 mmol) in acetone (20 mL) was
treated with J ones reagent (CrO3/H2SO4) until the orange color
persisted, quenched with isopropyl alcohol, and partitioned
between ethyl acetate and water. The organic layer was
washed with water, dried (Na2SO4), filtered, concentrated, and
purified on silica gel with a gradient of 30% ethyl acetate/
hexanes to 10% MeOH/dichloromethane to provide 1.27 g
(86%) 2-(2-carboxyethyl)naphthalene-1-carboxylic acid allyl
ester (58a ) as a yellow oil. MS (ESI) m/e 283 (M - H)-.
A solution of 58a (600 mg, 2.11 mmol) in benzene (5 mL)
was treated with thionyl chloride (0.184 mL, 2.53 mmol) at
room temperature and allowed to stir for 1 h. The reaction
mixture was concentrated to dryness, redissolved in benzene
(5 mL), treated with CH2N2/Et2O at 0 °C, and allowed to stir
at room temperature for 2 h. The reaction mixture was
concentrated under a stream of nitrogen, and the residue was
dissolved in methanol (30 mL), treated with silver benzoate
(1.1 g, 4.85 mmol) and triethylamine (11 mL, 79.7 mmol), and
allowed to stir at room temperature for 1.5 h. The organic layer
was partitioned between saturated sodium bicarbonate and
ethyl acetate, dried (Na2SO4), filtered, concentrated, and
purified on silica gel with 10% ethyl acetate/hexanes to provide
402 mg (61%) of methyl 1-[(2-propenyloxy)carbonyl]-2-naph-
thalenebutanoate as an yellow oil. MS (DCI) m/e 330 (M +
NH4)+.
A solution of ester (400 mg, 1.28 mmol) in isopropyl alcohol
(5 mL) was treated with lithium hydroxide (1.0 M, 1.28 mL,
1.28 mmol), stirred at room temperature for 1.5 h, and
partitioned between ethyl acetate and water. The aqueous
layer was then acidified with 1 N HCl, extracted with dichlo-
romethane, dried (Na2SO4), filtered, and concentrated to
provide 282.8 mg (74%) of 2-(2-carboxypropyl)naphthalene-1-
carboxylic acid allyl ester (58b) as a yellow oil. MS (ESI) m/e
299 (M + H)+, 297 (M - H)-, 321 (M + Na)+.
1H NMR (DMSO-d6) δ 2.008-2.037 (m, 2H), 2.799-2.830 (t,
2H, J ) 4.5 Hz), 3.072-3.101 (t, 2H, J ) 4.2 Hz), 3.813 (s,
3H), 7.049-7.066 (d, 2H, J ) 5.1 Hz), 7.553-7.558 (3H),
7.694-7.711 (d, 2H, J ) 5.1 Hz), 7.758-7.784 (3H), 7.906-
7.935 (t, 2H, J ) 3.9 Hz), 7.997-8.014 (d, 2H, J ) 5.1 Hz),
9.223 (s, 1H), 10.974 (s, 1H); HRMS (FAB) calculated m/e for
(M + H)+: C28H26NO4, 440.1862. Found 440.1882.
Syn th esis of 2-[[2-(4′-Ch lor o[1,1′-bip h en yl]-4-yl)su lfo-
n yl]eth oxy]-N-h yd r oxy-1-n a p h th a len eca r boxa m id e (26,
Scheme 5). A solution of 2-hydroxy-1-carboxynaphthalene (4.70
g, 25.0 mmol) and 20% cesium carbonate (20.3 mL, 12.5 mmol)
in methanol (20 mL) was stripped to dryness, dissolved in DMF
(10 mL), treated with benzyl bromide (2.67 mL, 22.5 mmoL),
stirred for 20 h, diluted with brine, and extracted with ethyl
acetate. The ethyl acetate was washed with water, 1 M NaOH,
water, and brine, dried (MgSO4), filtered, and concentrated to
provide 3.98 g (57%) of 2-hydroxynaphthalene-1-carboxylic acid
benzyl ester (38). MS (DCI/NH3) m/e 279 (M + H)+.
A solution of 4-bromothiophenol (4.72 g, 25.0 mmol) in DMF
(20 mL) was treated with sodium hydride (1.10 g, 27.4 mmol),
stirred for 30 min, treated with bromoethanol (1.95 mL, 27.4
mmol), stirred for 20 h, treated with aqueous ammonium
chloride, and extracted with ethyl acetate. The organic layer
was washed with water and brine, dried (MgSO4), filtered, and
concentrated. The residue was purified on silica gel with 30%
ethyl acetate/hexanes to provide 5.06 g (87%) of 2-(4-bro-
mophenylsulfanyl)ethanol (44a ). MS (DCI/NH3) m/e 232 (M
+ H)+.
2-(4′-Chlorobiphenyl-4-ylsulfanyl)ethanol (44b) was pre-
pared from 45a using 4-chlorophenylboronic acid and the
described conditions for procedure A. MS (DCI/NH3) m/e 265
(M + H)+.
A solution of 44b (0.50 g, 1.89 mmol) and triethylamine (0.39
mL, 2.84 mmol) in CH2Cl2 (10 mL) at 0 °C was treated with
methanesulfonyl chloride (0.18 mL, 2.27 mmol). After 1 h, the
reaction mixture was washed with 0.5 M HCl, water, and
brine, dried (MgSO4), filtered, and concentrated. The residue
was dissolved in DMF (1 mL) and added to a solution of 38
(0.58 g, 2.08 mmol) and sodium hydride (0.087 g, 2.20 mmol)
in DMF (6 mL) at 0 °C. The mixture was heated to 50 °C for
4 h, cooled, washed with brine, dried (MgSO4), filtered,
concentrated, and purified on silica gel using 20% ethyl
acetate/hexanes to provide 0.49 g (50%) of 2-[2-(4′-chlorobi-
phenyl-4-ylsulfanyl)ethoxy]naphthalene-1-carboxylic acid ben-
zyl ester (45d ). MS (DCI/NH3) m/e 525 (M + H)+.
A solution of 45d (0.42 g, 0.75 mmol) and 3-chloroperoxy-
benzoic acid (0.65 g, 3.76 mmol) in methylene chloride (50 mL)
was heated at reflux for 16 h, washed with aqueous sodium
bisulfite, aqueous sodium bicarbonate, water, and brine, dried
(MgSO4), filtered, and concentrated. Recrystallization from
ethyl acetate/hexanes provided 0.18 g (43%) of 2-[2-(4′-chlo-
robiphenyl-4-sulfonyl)ethoxy]naphthalene-1-carboxylic acid ben-
zyl ester (46d ). MS (DCI/NH3) m/e 574 (M + NH4)+.
A mixture of a solution of 46d (0.18 g, 0.32 mmol) in 20%
acetic acid-THF and 10% palladium-carbon (0.050 g) was
stirred at room temperature under an atmosphere of hydrogen
for 20 h, filtered, and concentrated to provide 0.086 g (58%) of
2-[2-(4′-chlorobiphenyl-4-sulfonyl)ethoxy]naphthalene-1-car-
boxylic acid (47d ). MS (DCI/NH3) m/e 484 (M + NH4)+.
The carboxylate intermediate 47d was converted to the
titled compound 26 following procedure B. MS (DCI/NH3) m/e
482 (M + H)+; 1H NMR(DMSO-d6) δ 4.87 (m, 2H), 4.46 (m,
2H), 7.41 (m, 2H), 7.56 (m, 4H), 7.78 (m, 3H), 7.98 (m, 5H),
9.20 (s, 1H), 11.02 (s, 1H). Anal. Calcd for C25H20ClNO5S: C,
62.30; H, 4.18; Cl, 7.36; N, 2.91. Found: C, 61.96; H, 4.45; N,
2.66.
A solution of 58b (282 mg, 0.953 mmol) in benzene (5 mL)
was treated with thionyl chloride (0.138 mL, 1.89 mmol) and
DMF (1 drop), stirred at room temperature for 30 min,
concentrated to dryness, and redissolved in dichloromethane
(5 mL). The resulting solution was treated with 4-methoxy-
biphenyl (355 mg, 1.89 mmol) and aluminum chloride (377 mg,
2.84 mmol) at 0 °C, stirred at room temperature for 40 min,
quenched with ice-water, extracted with dichloromethane,
dried (Na2SO4), filtered, concentrated, and purified on silica
gel with a gradient of 5% to 20% ethyl acetate/hexanes to
provide 200 mg (45%) of 2-[4-(4′-methoxybiphenyl-4-yl)-4-
oxobutyl]naphthalene-1-carboxylic acid allyl ester (59b) con-
taminated with 30% of the ortho-substituted isomer. MS
(APCI) m/e 535 (M + H)+, 552 (M + NH4)+.
A solution of 59b (200 mg, 0.431 mmol) in dichloromethane
(5 mL) at room temperature was treated with tetrakis(triphen-
ylphosphine)palladium (43 mg, 0.0375 mmol), triphenylphos-
phine (19.6 mg, 0.075 mmol), and piperidine (0.0454 mL, 0.452
mmol) and allowed to stir at room temperature for 30 min.
The reaction mixture was diluted with 0.5 N HCl and extracted
with dichloromethane. The organic layer was dried (Na2SO4),
filtered, concentrated, and purified on silica gel with 10%
methanol/CH2Cl2 to provide 197 mg (100%) 2-[4-(4′-methoxy-
biphenyl-4-yl)-4-oxobutyl]naphthalene-1-carboxylic acid (60b)
as a white solid. MS (ESI) m/e 425 (M + H)+, 423 (M - H)-,
454 (M + Na)+.
Syn th esis of N-Hyd r oxy-2-[2-[[3′-(cya m om eth yl)[1,1′-
b ip h en yl]-4-yl]su lfon yl]et h oxy]-1-n a p h t h a len eca r b ox-
a m id e (27, Scheme 5). The title compound was prepared
according to the procedure described for the preparation of 22,
substituting 3-cyanomethylphenyl boronic acid in place of
4-methoxyboronic acid. MS (ESI +) m/e 487 (M + H)+; 1H NMR
(DMSO-d6) δ 3.90 (d, J ) 6 Hz, 2H), 4.13 (s, 2H), 4.47 (d,J )
6 Hz, 2H), 7.38-7.60 (m, 5H), 7.68-7.75 (m, 3H), 7.88 (d, J )
The carboxylate intermediate 60b was converted to the
titled compound 25 following procedure B. mp 160-163 °C
decomposed; MS (APCI) m/e 440 (M + H)+, 457 (M + NH4)+;

5638 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
Hajduk et al.
8 Hz, 1H), 7.92-7.98 (m, 3H), 8.06 (d, J ) 8 Hz, 1H), 9.20 (d,
J ) 1.5 Hz, 1H). Anal. Calcd for C27H22N2O5S‚0.2 H2O: C,
66.16; H, 4.61,:N, 5.72. Found: C, 65.84; H, 4.64: N, 5.50.
ethyl acetate (100 mL), washed with H2O and brine, dried
(Na2SO4), filtered, and concentrated. Purification over silica
gel with 30% hexanes/CH2Cl2 provided 1.19 g (77%) of N-Z-2-
[(4′-trifluoromethoxybiphenyl-4-sulfonylamino)methyl]naph-
thalene-1-carboxylic acid tert-butyl ester (55a ). MS (ESI) m/e
709 (M + NH4)+; 1H NMR (CDCl3) δ 1.71 (s, 9H), 5.13 (s, 2H),
5.38 (s, 2H), 7.05-7.40 (m, 8H), 7.47-7.62 (m, 6H), 7.75-7.86
(m, 4H), 8.01 (d, 1H); HRMS (FAB) calculated m/e)692.1930
for (M + H)+ for C37H33F3NO7S. Found m/e ) 692.1941.
A solution of 55a (1.19 g, 1.72 mmol) in CH2Cl2 (35 mL)
under N2 at -20 °C was treated with trifluoroacetic acid (13.3
mL, 0.172 mol) and allowed to stir at 0 °C for 1 h and then
quenched with 2.6 M Na2CO3 (50 mL). The reaction mixture
was reacidified to pH 3 with 1 M aq HCl and extracted with
ethyl acetate. The combined ogranic layers were washed with
brine, dried (Na2SO4), filtered, and concentrated (chasing with
anhydrous toluene) to provide 1.096 g (100%) of 2-[(4′-trifluo-
romethoxybiphenyl-4-sulfonylamino)methyl]naphthalene-1-
carboxylic acid (56a ). MS (APCI) m/e 653 (M + NH4)+, 636 (M
+ H)+; 1H NMR (CDCl3) δ 5.09 (s, 2H), 5.41 (s, 2H), 7.05-7.25
(m, 5H), 7.33 (d, J ) 8.8 Hz, 2H), 7.48 (d, J ) 8.5 Hz, 2H),
7.52-7.65 (m, 5H), 7.79 (d, J ) 8.8 Hz, 2H), 7.88 (m, 1H), 7.95
(d, J ) 8.5 Hz, 1H), 8.16 (d, 1H); HRMS (FAB) calculated
636.1304 for (M + H)+ for C33H25F3NO7S. Found 636.1318.
Syn th esis of N-Hyd r oxy-2-[[[4′-(tr iflu or om eth oxy)[1,1′-
b ip h en yl]-4-yl]su lfon yla m in o]m et h yl]-1-n a p h t h a len e-
ca r boxa m id e (28, Scheme 7). A solution of 1-bromo-2-
naphthaldehyde (2.12 g, 8.91 mmol) in MeOH under N2 at 0
°C was treated with NaBH4 (0.51 g, 13.4 mmol), stirred for 15
min, quenched with acetone, and concentrated. Purification
on silica gel with 5% ethyl acetate/CH2Cl2 provided 1.95 g
(92%) of (1-bromonaphthalen-2-yl)methanol (50) as a white
solid. mp 101-102 °C; MS (DCI) m/e 256/254 (M + NH4)+; 1H
NMR (CDCl3) δ 2.09 (br d, 1H), 5.00 (s, 2H), 7.50-7.70 (m,
3H), 7.85 (d, J ) 8.8 Hz, 2H), 8.32 (d, J ) 8.9 Hz, 1H).
A suspension of 4-bromophenylsulfonamide (3.5 g, 14.8
mmol) and di-tert-butyl dicarbonate (3.76 g, 17.0 mmol) in
CH2Cl2 (100 mL) under nitrogen was treated with triethyl-
amine (2.3 mL, 16.3 mmol) and DMAP (183 mg, 1.48 mmol)
and stirred at room temperature for 12 h. The reaction mixture
was washed with 1 M HCl (2 × 25 mL), H2O (25 mL), and
brine, dried (Na2SO4), filtered, and concentrated. Purification
on silica gel with a gradient of 2% to 5% MeOH in CH2Cl2
afforded 4.46 g (90%) of N-Boc-4-bromobenzenesulfonamide as
a white solid. mp 127-128 °C; MS (DCI) m/e 355/353 (M +
1
NH4)+; H NMR (CDCl3) δ 1.41 (s, 9H), 7.16 (br s, 1H), 7.69
To an ice cold solution of 56a (1.096 g, 1.72 mmol) in
CH2Cl2 (12 mL) under N2 were added DMF (5 drops) and oxalyl
chloride (0.30 mL, 3.45 mmol), and the reaction was allowed
to stir at room temperature for 1 h. The solvent was then
removed by rotary evaporation chasing with anhydrous toluene
(5 mL), and the residue was taken up in CH2Cl2 (7 mL) and
added to a 0 °C solution of hydroxylamine hydrochloride (1.21
g, 0.017 mol) and triethylamine (2.9 mL, 0.021 mol) in THF/
H2O (2:1 v/v, 12 mL). After allowing the reaction mixture to
stir at room temperature for 3 h, ethyl acetate (100 mL) and
H2O (25 mL) were added, the layers were separated, and the
organic phase was washed with 1 M HCl (2 × 10 mL),
saturated aqueous NaHCO3 (10 mL), and brine, dried
(Na2SO4), filtered, and concentrated. The residue was tritu-
rated with CH2Cl2 (75 mL) and vacuum filtered to remove a
solid impurity. The filtrate was concentrated and the residue
purified on silica gel (1.9 × 6 cm) with a gradient of CH2Cl2 to
3% MeOH/CH2Cl2 + 0.5% concentrated NH4OH to obtain 0.459
g (41%) of N-hydroxy-2-[[[[4′-(trifluoromethoxy)[1,1′-biphenyl]-
4-yl]sulfonyl](phenylmethoxycarbonyl)amino]methyl]-1-naph-
thalenecarboxamide. MS (ESI) m/e 668 (M + NH4)+, 651 (M
+ H)+; 1H NMR (CDCl3) δ 5.05 (s, 2H), 5.22 (br s, 2H), 7.04 (d,
J ) 7.3 Hz, 2H), 7.18 (t, J ) 7.3 Hz, 2H), 7.28-7.39 (m, 3H),
7.42 (d, J ) 7.7 Hz, 2H), 7.50-7.60 (m, 4H), 7.64 (d, J ) 8.4
Hz, 1H), 7.74 (d, J ) 8.1 Hz, 2H), 7.84-8.02 (m, 3H), 9.19 (br
s, 1H); HRMS (FAB) calculated 651.1413 for (M + H)+ for
(d, 2H), 7.89 (d, 2H).
A mixture of N-Boc-4-bromobenzenesulfonamide (3.10 g,
9.22 mmol), 4-trifluoromethoxyphenylboronic acid (2.13 g,
10.14 mmol), absolute EtOH (15 mL), 2 M aqueous Na2CO3
(9.22 mL, 18.44 mmol), and toluene (65 mL) was sparged with
N2, treated with tetrakis(triphenylphosphine)paladium (538
mg, 0.461 mmol), and heated at reflux for 1.25 h. The reaction
mixture was cooled, diluted with H2O (50 mL) and ethyl ace-
tate (100 mL), and acidified to pH 3 with HOAc. The organic
phase was washed with H2O and brine, dried (Na2SO4),
filtered, and concentrated. Purification on silica gel with a
gradient of CH2Cl2 to 2% MeOH/CH2Cl2 provided 3.40 g (88%)
of N-Boc-4′-trifluoromethoxybiphenyl-4-sulfonamide (51) as a
white solid. MS (DCI) m/e 435 (M + NH4)+; 1H NMR (DMSO-
d6) δ 1.31 (s, 9H), 7.54 (d, J ) 8.8 Hz, 2H), 7.90 (d, J ) 8.8 Hz,
2H), 7.96 (s, 4H).
To a solution of 51 (3.37 g, 8.06 mmol) in THF (75 mL) under
N2 were added triphenylphosphine (5.34 g, 20.16 mmol), 50
(1.59 g, 6.72 mmol), and diethyl azodicarboxylate (DEAD) (2.8
mL, 16.80 mmol), and the reaction was allowed to stir for 24
h. The solvent was removed, and the material was purified
on silica gel with a gradient of 50% to 40% hexanes/CH2Cl2 to
provide 3.81 g (89%) of N-Boc-2-[(4′-trifluoromethoxy-biphenyl-
4-sulfonylamino)methyl]-1-bromonaphthalene (53a). MS (APCI)
m/e 655/653 (M + NH4)+; 1H NMR (CDCl3) δ 1.32 (s, 9H), 5.38
(s, 2H), 7.31-7.87 (m, 11H), 8.00 (d, J ) 8.5 Hz, 2H), 8.32 (d,
J ) 8.5 Hz, 1H).
C
33H26F3N2O7S. Found 651.1418.
A mixture of benzyl ester (0.456 g, 0.70 mmol) and 5% Pd-C
(100 mg) in MeOH (10 mL) at 0 °C was hydrogenated under 1
atm of hydrogen for 2 h. The catalyst was removed by vacuum
filtration through a 0.5 m poly(tetrafluoroethylene) (PTFE)
membrane, and the filtrate was concentrated. Recrystallization
from ethyl acetate/hexane provided 0.19 g (52%) of 28 as a
white solid. MS (ESI) m/e 539 (M + Na)+, 534 (M + NH4)+,
To a solution of 53a (1.50 g, 2.36 mmol) in THF (25 mL)
under N2 at -78 °C was added tert-butyllithium (1.7 M in
pentane, 3.0 mL, 5.10 mmol). The resulting reddish-purple
solution was stirred for 30 min at the same temperature and
then quenched with HOAc (0.56 mL, 9.77 mmol) and warmed
to room temperature. The solvent was removed, and the
resulting oil was dissolved in ethyl acetate (100 mL), washed
with H2O and brine, dried (Na2SO4), filtered, and concentrated.
Purification on silica gel with a gradient of 10% hexanes/
CH2Cl2 to 3% ethyl acetate/CH2Cl2 provided 1.13 g (86%) of
2-{[methyl-(4′-trifluoromethoxybiphenyl-4-sulfonyl)amino]-
methyl}naphthalene-1-carboxylic acid tert-butyl ester (54a ).
MS (DCI) m/e 575 (M + NH4)+; 1H NMR (CDCl3) δ 1.57 (s,
9H), 4.26 (d, J ) 6.4 Hz, 2H), 5.32 (t, J ) 6.4 Hz, 1H), 7.29-
7.96 (m, 14H); HRMS (FAB) calculated 558.1562 for (M + H)+
for C29H27F3NO5S. Found 558.1543.
1
517 (M + H)+; H NMR (CD3OD) δ 4.29 (s, 2H), 7.39 (d, J )
8.4 Hz, 2H), 7.47-7.60 (m, 3H), 7.70-7.79 (m, 4H), 7.81-7.90
(m, 3H), 7.95 (d,
J
) 8.1 Hz, 2H). Anal. Calcd for
C
25H19F3N2O5S: C, 58.13; H, 3.71; N, 5.42. Found: C, 57.88;
H, 3.75; N, 5.39.
Syn th esis of 2-[2-[(4′-Ch lor o[1,1′-bip h en yl]-4-yl)su lfo-
n yl]et h yl]-N-h yd r oxy-1-n a p h t h a len eca r b oxa m id e (29,
Scheme 9). A solution of 4-chloro-4′-methyl sulfone biphenyl
(0.24 g, 0.88 mmol) in THF (25 mL) was treated with n-BuLi
(0.35 mL, 0.88 mmoL) and stirred and -78 °C for 15 min to
produce the lithiosulfone. A solution of 61 (0.25 g, 0.88
mmoL)19 in THF (5 mL) was added dropwise to the lithiosul-
fone and stirred at ambient temperature for 16 h, poured into
water, and extracted with ethyl acetate. The organic extracts
were washed with brine, dried (MgSO4), filtered, and concen-
trated. Purification on silica gel with 20% ethyl acetate/
A solution of example 54a (1.255 g, 2.25 mmol) in DMF (20
mL) under N2 at 0 °C was treated with NaH (60% dispersion
in mineral oil, 180 mg, 4.50 mmol) and allowed to stir for 30
min. Benzyl chloroformate (0.68 mL, 4.50 mmol) was added,
the mixture was allowed to stir for 2 h, and HOAc was added.
The solvent was removed, and the residue was dissolved in

Matrix Metalloproteinase Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5639
that Blocks Cartilage Degradation in Rabbits. J . Med. Chem.
1997, 40, 2525-2532.
(7) Singh, J .; Conzentino, P.; Cundy, P.; Gainor, J . A.; Gilliam, C.
L. et al. Relationship Between Structure and Bioavailability in
hexanes provided 0.12 g (29%) of 2-[2-[(4′-chloro[1,1′-biphenyl]-
4-yl)sulfonyl]ethyl]-1-naphthalenecarboxylic acid methyl ester
(62).
To a solution of 62 (0.12 g, 0.26 mmoL) in MeOH (3
mL), H2O (3 mL), and THF (15 mL) was added LiOH‚H2O (0.17
g, 3.84 mmoL). The mixture was stirred at 80 °C for 16 h,
poured into H2O, and extracted with ethyl acetate. The
combined organic extracts were washed with brine, dried
(MgSO4), filtered, and concentrated. Purification on silica gel
with 2% MeOH/CH2Cl2 provided 0.02 g (20%) of 2-[2-[(4′-
chloro[1,1′-biphenyl]-4-yl)sulfonyl]ethyl]-1-naphthalenecarbox-
ylic acid (63).
a
Series of Hydroxamate Based Metalloprotease Inhibitors.
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(8) Summers, J . B.; Gunn, B. P.; Mazdiyasni, H.; Goetze, A. M.;
Young, P. R. et al. J . Med. Chem. 1987, 30, 2121-2126.
(9) Peng, S. X.; Strojnowski, M. J .; Hu, J . K.; Smith, B. J .; Eichhold,
T. E. et al. Gas Chromatographic-Mass Spectrometric Analysis
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Inhibitors in Rat and Human Liver Microsomes. J . Chromatogr.
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(10) Hajduk, P. J .; Gomtsyan, A.; Didomenico, S.; Cowart, M.;
Bayburt, E. K. et al. Design of Adenosine Kinase Inhibitors from
the NMR-Based Screening of Fragments. J . Med. Chem. 2000,
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(15) It should be noted that the inhibitory activity observed in the
blood during the PK studies cannot formally be attributed to
the parent compound, as an active metabolite could also
contribute to enzymatic inhibition. However, the most likely
metabolite would be the corresponding carboxylic acid, which
would be predicted to have little or no activity (See ref 2). In
fact, the carboxylic analogue of the initial inhibitor 3 exhibited
a more than 100-fold loss in potency compared to the hydrox-
amate-containing parent (ref 12).
The carboxylate intermediate 63 was converted to the titled
compound 29 following procedure B. mp 115 °C; MS (ESI) m/e
534 (M - H)+, 536 (M + H)+, 558 (M + Na)+; 1H NMR (DMSO-
d6) δ 10.98 (s, 1H), 9.30 (s, 1H), 8.04-7.39 (m, 14H), 3.74-
3.68 (m, 2H), 3.11-3.01 (m, 2H); HRMS Calculated for
C
25H21NO4ClS: 536.0880. Found: 536.0880.
Syn th esis of N-Hyd r oxy-2-[4-(4′-m eth oxy[1,1′-bip h en -
yl]-4-yl)-3-oxop r op yl]-1-n a p h t h a len eca r b oxa m id e (30,
Scheme 8). 58a was converted to 30 as described for the
conversion of 58b to 25. MS (APCI) m/e 426 (M + H)+, 448 (M
1
+ Na)+; H NMR (DMSO-d6) δ 3.00-3.11 (t, 2H, J ) 9 Hz),
3.40-3.50 (m, 2H), 3.81 (s, 0.8H), 3.89 (s, 0.2H), 7.02-7.09 (d,
2H, J ) 9 Hz), 7.23-7.97 (10H), 8.79-8.06 (d, 2H, J ) 3 Hz),
9.31 (s, 1H), 11.05 (s, 1H). Anal. Calcd for C27H23NO4‚0.75
MeOH, C, 74.14; H, 5.83; N, 3.11. Found: C, 74.08; H, 5.83;
N, 2.73.
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