Matrix metalloproteinases (MMPs) are a group of calcium-dependent zinc-endopeptidases engaged in the degradation and remodeling of extracellular matrix. S-3304 is a non-cytotoxic and orally-active inhibitor for MMP-2 and MMP-9, but not MMP-1, MMP-3 and MMP-7[1]. S-3304 completely inhibited the gelatinase activity of MMP-2 and MMP-9 derived from human tumor cells. In mice implanted with HT1080 human fibrosarcoma cells-filled chamber, oral administration of S-3304 (20 and 200 mg/kg, b.i.d) suppressed tumor-induced angiogenesis as shown as decreased number and vascular area of vessels beneath the cutaneous muscle[2]. In the metabolism and pharmacokinetic studies of S-3304, the plasma radioactivity was abruptly elevated by orally administration of [14C]-S-3304 with Tmax of 1.5 hr in rats and 0.6 hr in mice, and eliminated with T1/2 of 3.5 hr in rats and 5.7 hr in mice. The dose-linearity of AUC after the oral administration of S-3304 was found at the doses of 30 mg/kg in rats and 10 mg/kg in mice. The absolute bioavailability of S-3304 was 32% in rats and 34% in mice[3].
作用机制
S-3304 is a D-tryptophan derivative that potently inhibits MMP-2 and MMP-9. The inhibitory activity are greatly affected by the structure of sulfonamide moiety in MMPs[4].
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