生物活性

• 描述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].

• 动物研究
  剂量	Mice: 20 mg/kg - 200 mg/kg[2] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00033215	Solid Tumors	Phase 1	Completed	-	United States, Colorado ... more >> University of Colorado Hospital Denver, Colorado, United States, 80262 United States, Florida H. Lee Moffitt Concer Center and Research Institute Tampa, Florida, United States, 33612 United States, New York Roswell Park Cancer Center Buffalo, New York, United States, 14263 United States, Ohio Cleveland Clinic Foundation Cleveland, Ohio, United States, 44195 Collapse <<
  NCT00033566	Unspecified Adult Solid Tumor,... more >> Protocol Specific Collapse <<	Phase 1	Completed	-	United States, New York ... more >> Roswell Park Cancer Institute Buffalo, New York, United States, 14263-0001 Collapse <<
  NCT00078390	Non Small Cell Lung Cancer ... more >> Lung Cancer Stage IIIA Non Small Cell Lung Cancer Stage IIIB Non Small Cell Lung Cancer Collapse <<	Phase 1 Phase 2	Completed	-	United States, California ... more >> Scripps Cancer Institute La Jolla, California, United States, 92037 United States, District of Columbia Lombardi Cancer Center Washington, District of Columbia, United States, 20007 United States, Kansas University of Kansas Cancer Center Kansas City, Kansas, United States, 66160 United States, New Jersey VA Medical Center-East Orange (study available to veterans only) East Orange, New Jersey, United States, 07108 United States, Ohio The Cleveland Clinic Cleveland, Ohio, United States, 44195 Collapse <<

• 参考文献

• [1] Chiappori AA, Eckhardt SG, Bukowski R, Sullivan DM, Ikeda M, Yano Y, Yamada-Sawada T, Kambayashi Y, Tanaka K, Javle MM, Mekhail T, O'bryant CL, Creaven PJ. A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors. Clin Cancer Res. 2007 Apr 1;13(7):2091-9.

  [2] In vitro pharmacological profiles and in vivo anti-angiogenesis activity of S-3304, a novel matrix metalloproteinase inhibitor

  [3] Non-clinical assessments of drug metabolism and pharmacokinetics of S-3304, a matrix metalloproteinase inhibitor

  [4] Tamura Y, Watanabe F, Nakatani T, Yasui K, Fuji M, Komurasaki T, Tsuzuki H, Maekawa R, Yoshioka T, Kawada K, Sugita K, Ohtani M. Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives. J Med Chem. 1998 Feb 12;41(4):640-9.