J. I. Levin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 239±242
241
approximately a 100-fold increase in potency against
MMP-9. The two bromothiophenes, 11a and 11b, were
both moderately potent versus MMP-9. As in the anthra-
nilic acid series, the N-picolyl sulfonamide is somewhat
more active than the N-benzyl derivative. The alkynyl
substituent of thiophene 13 is less eective at increasing
potency, perhaps due to its smaller steric bulk. None of
the thiophene hydroxamic acids approached the level of
MMP inhibition achieved by the anthranilic acid hydro-
xamic acids (see 1a, Table 1). The picolyl derivative 11b
was inactive on oral dosing at 100 mg/kg against MMP-9
in the rat dialysis implant bioactivity model.
Scheme 4. (i) 4-MeOPhSO2Cl, TEA; (ii) (Me)2NCH(OtBu)2; (iii)
BnBr, NaH; (iv) TFA; (v) (a) (COCl)2, DMF, (b) NH2OH.
Biology
The pyrazole analogue 9d was only weakly active
against MMP-9 even with the methyl group on the pyr-
azole nitrogen acting as the requisite second substituent
adjacent to the sulfonamide nitrogen. The electron de®-
cient nature of the pyrazole ring may be responsible for
the diminished in vitro activity of 9d relative to the
electron rich thiophenes.
All of the hydroxamic acid ®nal products were tested in
vitro7,8 for their ability to inhibit MMP-9. Inhibitors of
MMP-9 are postulated to have utility as inhibitors of
tumor metastasis. Most compounds were also tested
against the collagenases MMP-1 and MMP-13, which
are presumed to be important in the etiology of osteo-
arthritis. The in vitro potencies of these compounds are
shown in Table 1.
The cyclohexyl analogues 16a and 16b are also less active
than the anthranilic acid hydroxamic acids 1a and 1b ver-
sus both MMP-9 and MMP-13. The trans-cyclohexyl
derivative is more potent than the cis-isomer against
MMP-1, MMP-9, and MMP-13. The level of activity
for the trans-cyclohexyl analogue, 16a, is somewhat
high, however, in light of the fact that the correspond-
ing anthranilic acid analogue lacking a 3-substituent (1,
R1=Bn, R2=H) is a 555 nM inhibitor of MMP-13.
Pyridine analogue 2 is a potent inhibitor of both MMP-9
and MMP-13 with moderate selectivity over MMP-1.
Compounds with this selectivity pro®le may be useful in
assessing the basis of musculoskeletal side eects seen in
clinical trials of some MMP inhibitors.9 Pyridine 2 is
almost 3-fold more potent against MMP-13 than the
corresponding 3-methoxy anthranilic acid analogue (1b,
Table 1), and much more selective over MMP-1. The rea-
son for this apparent increase in potency is not known.
Compound 2 is also a moderately potent inhibitor of
TNF-a converting enzyme (TACE), with an IC50 of 294
nM.10 Unfortunately, compound 2 was not orally active
against MMP-13 at a dose of 50mg/kg in the rat dialysis
implant bioactivity model.11
In conclusion, we have investigated the pyridyl, thio-
phene, pyrazole and cyclohexyl analogues of the anthra-
nilate hydroxamate class of MMP inhibitors. The pyridyl
derivative 2 is more potent and selective in vitro than
the related anthranilate 1b. The thiophene and pyrazole
rings proved to be less satisfactory replacements for the
phenyl ring of the anthranilate hydroxamic acids. It is
unclear whether the decrease in potency observed for
these two scaolds is due to electronic or steric eects.
The cyclohexyl ring is also a less eective scaold for the
sulfonamide-hydroxamate pharmacophore, although
incorporating additional substituents on the cycloalkyl
ring might provide more active compounds. Two of the
compounds (2 and 11b) were tested in vivo and were
inactive at the dose tested.
The thiophene derivatives 9a and 9b, lacking a second
substituent adjacent to the sulfonamide nitrogen were
very weakly active versus MMP-9 in accord with the SAR
previously shown for the anthranilic acid derivatives. As
expected, incorporation of a methyl substituent next to
the sulfonamide nitrogen in thiophene 9c provides
Table 1. In vitro potency of sulfonamide-hydroxamic acids
Compound
MMP-1a
MMP-9a
MMP-13a
References and Notes
1a (R1=CH2-3-Py, R2=Me)
1b (R1=CH2Ph, R2=OMe)
2
9a
9b
9c
9d
11a
11b
13
16a
16b
143
520
1227
5
23
15
8
138
47
NTc
NT
NT
NT
427
290
1. (a) Clark, I. M.; Rowan, A. D.; Cawston, T. E. Curr. Opin.
Anti-In¯ammat. Immunomodulat. Investigat. Drugs 2000, 2, 16.
(b) Shaw, T.; Nixon, J. S.; Bottomley, K. M. Exp. Opin.
Invest. Drugs 2000, 9, 1469. (c) Bottomley, K. M.; Johnson,
W. H.; Walter, D. S. J. Enzyme Inhib. 1998, 13, 79.
2. (a) Yip, D.; Ahmad, A.; Karapetis, C. S.; Hawkins, C. A.;
Harper, P. G. Investigat. New Drugs 1999, 17, 387. (b) Nelson,
A. R.; Fingleton, B.; Rothenberg, M. L.; Matrisian, L. M. J.
Clin. Oncol. 2000, 18, 1135.
3. (a) For recent comprehensive reviews, see: Montana, J.;
Baxter, A. Curr. Opin. Drug Disc. Devel. 2000, 3, 353. (b)
Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J. H.
Chem. Rev. 1999, 99, 2735. (c) Beckett, R. P.; Whittaker, M.
40% (1)b
19% (1)b
NT
67% (10)b
57% (10)b
104
22% (1)b
639
900
236
70
50% (1)b
49% (1)b 38% (0.3)b 35% (0.3)b
174
361
181
318
233
291
aIC50 (nM).
b% Inhibition (mM).
cNT=not tested.