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.