Water-Soluble MMP Inhibitor
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16 3501
(11) Poon, M.; Sun, J .; Marx, S. O.; Gallo, R.; Badimon, J . J .;
Taubman, M. B.; Marks, A. R. Rapamycin inhibits vascular
smooth muscle cell migration. J . Clin. Invest. 1996, 98, 2277-
2283. Sun, J .; Marx, S. O.; Chen, H.-J .; Poon, M.; Marks, A. R.;
Rabbani, L. E. Role for p27Kip1 in vascular muscle cell migration.
Circulation 2001, 103, 2967-2972.
(12) Marx, S. O.; Marks, A. R. The development of Rapamycin and
its application to stent restenosis. Circulation 2001, 104, 852-
855.
(13) Sierevogel, M. J .; Pasterkamp, G.; Velema, E.; de J aegere, P. P.
T.; de Smet, B. J . G. L.; Verheijen, J . H.; de Kleijn, D. P. V.;
Borst, C. Oral matrix metalloproteinase inhibition and arterial
remodeling after angioplasty. Circulation 2001, 103, 302-27.
Margolin, L.; Fishbein, I.; Banai, S.; Golomb, G.; Reich, R.; Perez,
L. S.; Gertz, S. D. Metalloproteinase inhibitor attenuates neoin-
tima formation and constrictive remodeling after angioplasty in
rats: augmentative effect of R$â3 receptor blockade. Atheroscleo-
sis 2002, 163, 269-277.
(14) Li, C.; Cantor, W. J .; Nili, N.; Robinson, R.; Fenkell, L.; Tran,
Y. L.; Whittingham, H. A.; Tsui, W.; Cheema, A. N.; Sparkes, J .
D.; Pritzker, K.; Levy, D. E.; Strauss, B. H. Arterial repair after
stenting and the effects of GM6001, a matrix metalloproteinase
inhibitor. J . Am. Col. Card. 2002, 39, 1852-1858.
(15) Yamada, A.; Uegaki, A.; Nakamura, T.; Ogawa, K. ONO-4817,
an orally active matrix metalloproteinase inhibitor, prevents
lipopolysaccharide-induced proteoglycan release from the joint
cartilage in guinea pigs. Inflamm. Res. 2000, 49, 144-146. Mori,
T.; Yamasaki, S.; Masui, F.; Matsuda, M.; Sasabe, H.; Zhou, Y.
F. Suppression of the development of experimentally induced
uterine adenomyosis by a novel matrix metalloproteinase inhibi-
tor, ONO-4817, in mice. Exp. Biol. Med. 2001, 226, 429-433.
Muraishi, Y.; Mitani, N.; Fuse, H.; Saiki, I. Effect of a matrix
metalloproteinase inhibitor (ONO-4817) on lung metastasis of
murine renal cell carcinoma. Anticancer Res. 2001, 21, 3845-
52. Sawada, S.; Murakami, K.; Yamaura, T.; Mitani, N.; Tsuka-
da, K.; Saiki, I. Therapeutic and analysis model of intrahepatic
metastasis reflects clinical behavior of hepatocellular carcinoma.
J pn. J . Cancer Res. 2002, 93, 190-197.
(16) Noguchi, T.; Yasuda, S.; Itoh, T.; Arai, T.; Kanda, K.; Tsutsui,
N.; Nakayama, Y.; Nonogi, H.; Matsuda, T. New multifunctional
percutaneous transluminal coronary angioplasty catheter device
capable of balloon infusion, local drug delivery and coronary
perfusion. J . Cardiol. 2000, 35, 41-45.
(17) Yasuda, S.; Noguchi, T.; Gohda, M.; Arai, T.; Tsutsui, N.;
Nakayama, Y.; Matsuda, T.; Nonogi, H. Local delivery of low-
dose docetaxel, a novel microtubule polymerizing agent, reduces
neointimal hyperplasia in a balloon-injured rabbit iliac artery
model. Cardiovasc. Res. 2002, 53, 481-486.
(18) Yasuda, S.; Kanna, M.; Sakuragi, S.; Kojima, S.; Nakayama, Y.;
Miyazaki, S.; Matsuda, T.; Kangawa, K.; Nonogi, H. Local
delivery of single low-dose of C-type natriuretic peptide, an
endogenous vascular modulator, inhibits neointimal hyperplasia
in a balloon-injured rabbit iliac artery model. J . Cardiovasc.
Pharmacol. 2002, 39, 784-788.
(19) Gottsauner-Wolf, M.; J ang, Y.; Penn, M. S.; Kaplan, A.; Ellis, S.
G.; Chisolm G. M.; Topol, E. J .; Lincoff, A. M. Quantitative
evaluation of local drug delivery using the infusa sleeve catheter.
Cathet. Cardiovasc. Diagn. 1997, 42, 102-108. Suzuki, T.; Kopia,
G.; Hayashi, S.; Baily, L. R.; Llanos, G.; Wilensky, R.; Klugherz,
B. D.; Papandreou, G.; Nayaran, P.; Leon, M. B.; Yeung, A. C.;
Tio, F.; Tsao, P. S.; Falotico, R.; Carter A. J . Stent-based delivery
of sirolimus reduces neointimal formation in a porcine coronary
model. Circulation 2001, 104, 1188-1193.
(20) ]Scozzafava, A.; Menabuoni, L.; Mincione, F.; Briganti, F.;
Mincione, G.; Supuran, C. T. Carbonic anhydrase inhibitors.
Synthesis of water-soluble, topically effective, intraocular pres-
sure-lowering aromatic/heterocyclic sulfonamides containing
cationic or anionic moieties: is the tail more important than the
ring? J . Med. Chem. 1999, 42, 2641-2650. Pouticello, G. S.;
Freedman, M. B.; Habecker, C. N.; Lyle, P. A.; Schwam, H.;
Varga, S. L.; Christy, M. E.; Randall, W. C.; Baldwin, J . J .
Thienothiopyran-2-sulfonamides: A novel class of water-soluble
carbonic anhydrase inhibitors. J . Med. Chem. 1987, 30, 591-
597.
main chain, -CH(CH3)CH2-), 2.12-2.14 (m, 8H, -CH(CH3)-),
2.31-2.98 (m, 848H, -N(CH3)2 and -OCOCH2CH2CONH-),
3.43-3.58 (m, 24H, -CONHCH2CH2OCO- and -CHCH2O-),
4.00 (m, 16H, -CHCH2O-), 6.95-7.03 (2d, 32H, J ) 8.4 Hz,
m-H of -COC6H4- and o-H of -OC6H5), 7.13 (t, 8H, J ) 8.4
Hz, p-H of -OC6H5), 7.33 (t, 16H, J ) 8.4 Hz, m-H of -OC6H5),
7.63 (d, 16H, J ) 8.4 Hz, o-H of -COC6H4-). The degree of
derivatization of MB unit was 5 mol % by UV spectral
measurement. Copolymer with 10 mol % of MB unit was
synthesized in a similar procedure by changing the monomer
ratio in the feed (data in the text).
Ack n ow led gm en t. We thank ONO Pharmaceutical
Co., Ltd. for a supply of ONO-M11-335 and measure-
ments of MMPI activity. This study was supported in
part by “Research Grants for Human Genome, Tissue
Engineering Food Biotechnology”, “Advanced Medical
Technology”, and “Aging and Health” from the Ministry
of Health, Labour and Welfare of J apan and by a Grant-
in-Aid for Scienific Research (B2-13450302, 2-14030095)
from the Ministry of Education, Science, Sports and
Culture of J apan.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectrum
of P A. This material is available free of charge via the Internet
at http://pubs.acs.org.
Refer en ces
(1) Massova, I.; Kotra, L. P.; Fridman, R.; Mobashery, S. Matrix
metaloproteinases: structures, evolution, and diversification.
FASEB J . 1998, 12, 1075-1095. Hidalgo, M.; Eckhardt, S. G.
Development of matrix metalloproteinase inhibitors in cancer
therapy. J . Natl. Cancer Inst. 2001, 93, 178-193.
(2) Dollery, C. M.; McEwan, J . R.; Henney, A. M. Matrix metallo-
proteinases and cardiovasucular disease. Circ. Res. 1995, 77,
863-868.
(3) Galis, Z. S.; Muszynski, M.; Sukhova, G. K.; Simon-Morrissey,
E.; Unemori, E. N.; Lark, M. W.; Amento, E.; Libby, P. Cytokine-
stimulated human vascular smooth muscle cells synthesized a
complement of enzymes required for extracellular matrix diges-
tion. Circ. Res. 1994, 75, 181-189.
(4) Nagase, H. Activation mechanisms of matrix metalloproteinases.
Biol. Chem. 1997, 378, 151-160.
(5) Sato, H.; Takino, T.; Okada, Y.; Cao, J .; Shinagawa, A.; Yama-
moto, E.; Seiki M. A matrix metalloproteinase expressed on the
surface of invasive tumour cells. Nature 1994, 370, 61-65.
(6) Baker, A. H.; Zaltsman, A. B.; George, S. J .; Newby, A. C.
Divergent effects of tissue inhibitor of metalloproteinase-1, -2
or -3 overexpression on rat vascular smooth muscle cell invasion,
proliferation, and death in vivo. J . Clin. Invest. 1998, 101, 1478-
1487.
(7) Supuran, C. T.; Scozzafava, A. In Matrix metalloproteinases
(MMPs) in proteinase and peptidase inhibition: Recent potential
targets for drug development; Smith, H. J ., Simons, C., Eds.;
Taylor & Francis: London & New York, 2002; pp 35-61.
Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J . Design
and therapeutic application of matrix metalloproteinase inhibi-
tors. Chem. Rev. 1999, 99, 2735-2776.
(8) Matter, H.; Schwab, W.; Barbier, D.; Billen, G.; Hasse, B.; Neises,
B.; Schudok, M.; Thorwart, W.; Schreuder, H.; Brachvogel, V.;
Lonze, P.; Weithmann, KU. Quantitative structure-activity
relationship of human neutrophil collagenase (MMP-8) inhibitors
using comparative molecular field analysis and X-ray structure
analysis. J . Med. Chem. 1999, 42, 1908-1920.
(9) Gavuzzo, E.; Pochetti, G.; Mazza, F.; Gallina, C.; Gorini, B.;
D’Alessio, S.; Pieper, M.; Tschesche, H.; Tucker, P. A. Two crystal
structures of human neutrophil collagenase, one complexed with
a prime- and the other with an unprimed-side inhibitor: impli-
cations for drug design. J . Med. Chem. 2000, 43, 3377-3385.
(10) J ia, MC.; Schwartz, M. A.; Sang, Q. A. Suppression of human
microvascular endothelial cell invasion and morphogenesis with
synthetic matrixin inhibitors. Targeting angiogenesis with MMP
inhibitors. Adv. Exp. Med. Biol. 2000, 476, 181-94. Graf von
Roedern, E.; Grams, F.; Brandstetter, H.; Moroder, L. Design
and synthesis of malonic acid-based inhibitors of human neu-
trophil collagenase (MMP8). J . Med. Chem. 1998, 41, 339-345.
(21) Knight, C. G.; Willenbrock, F.; Murphy, G. A novel coumarin-
labeled peptide for sensitive continuous assay of the matrix
metaloproteinases. FEBS Lett. 1992, 296, 263-266.
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