Development of a water-soluble matrix metalloproteinase inhibitor as an intra-arterial infusion drug for prevention of restenosis after angioplasty.
To prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) and/or stenting of atherosclerotic stenosed arteries, we designed and developed two water-soluble matrix metalloproteinases (MMPs) inhibitors. The first inhibitor was monomeric in type and was chemically synthesized by succinylation of the synthetic MMP inhibitor, N-hydroxy-5-hydroxy-2(S)-methyl-4(S)-(4-phenoxybenzoyl)aminopentanamide (ONO-M11-335). The second inhibitor was polymeric and was a radical copolymer of the vinyl derivative of ONO-M11-335 and a water-soluble monomer, N,N-dimethylacrylamide (DMAAm). For the second inhibitor, NMR analyses and UV-vis spectra measurements showed that the content of the ONO-M11-335 unit in the copolymers (M(n); ca. 10 000 and 20 000 by GPC measurements) was about 8 per molecule. The MMP inhibitors were all highly soluble in water, even under neutral pH. The succinylated derivative markedly inhibited MMP-2, MMP-9, and MMP-12 in vitro, as did ONO-M11-335. In contrast the copolymers, which can maintain effective plasma levels for extended periods by prevention of hepatic uptake, showed a ca. 100-fold reduced inhibition activity. Such water-soluble MMP inhibitors, developed in this study, may potentially be useful as an intra-arterial infusion drug for vascular injury.
Masuda
Takeshi
T
Department of Bioengineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
Nakayama
Yasuhide
Y
D000178:Acrylamides / Q000737:chemistry*; D015906:Angioplasty, Balloon, Coronary; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023903:Coronary Restenosis / Q000517:prevention & control*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D009682:Magnetic Resonance Spectroscopy; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D011108:Polymers; D011183:Postoperative Complications / Q000517:prevention & control; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D015607:Stents; D013237:Stereoisomerism; D014753:Vinyl Compounds / Q000737:chemistry*; D014867:Water
D000178:Acrylamides; D001549:Benzamides; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C476598:N-hydroxy-5-hydroxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D011108:Polymers; D011480:Protease Inhibitors; D014753:Vinyl Compounds; D014867:Water; C099046:N,N-dimethylacrylamide; D020782:Matrix Metalloproteinases