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A potent broad spectrum inhibitor of MMPs
Batimastat is a broad spectrum inhibitor of matrix metalloproteinases (MMP), with IC50 values of 1-5 nM for all MMPs tested, including MMP-1, -2, -3, -7, -9, -13, and -14.1,2,3,4 It also potently inhibits TNFα-converting enzyme (IC50 = 14.9 nM).2 Because of its action on MMPs, batimastat has anti-proliferative, anti-invasive, and anti-metastatic actions that are relevant, in particular, to cancer.5 Batimastat less effectively inhibits the processing of the low affinity IgE receptor CD23 (IC50 = 100 nM).6
1.Fray, M.J., Burslem, M.F., and Dickinson, R.P.Selectivity of inhibition of matrix metalloproteases MMP-3 and MMP-2 by succinyl hydroxamates and their carboxylic acid analogues is dependent on P3' group chiralityBioorg. Med. Chem. Lett.11(4)567-570(2001) 2.Fray, M.J., Dickinson, R.P., Huggins, J.P., et al.A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcersJ. Med. Chem.46(16)3514-3525(2003) 3.Sheppard, G.S., Florjancic, A.S., Giesler, J.R., et al.Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitorsBioorg. Med. Chem. Lett.8(22)3251-3256(1998) 4.Yamamoto, M., Tsujishita, H., Hori, N., et al.Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: An examination of the subsite pocketJ. Med. Chem.41(8)1209-1217(1998) 5.Chaudhary, A.K., Pandya, S., Ghosh, K., et al.Matrix metalloproteinase and its drug targets therapy in solid and hematological malignancies: An overviewMutat. Res.753(1)7-23(2013) 6.Bailey, S., Bolognese, B., Buckle, D.R., et al.Selective inhibition of low affinity IgE receptor (CD23) processingBioorg. Med. Chem. Lett.8(1)29-34(1998)
Animal experiment: | Mice[5] Six-weeks-old female BALB/c mice are used. Mice are treated i.p. with Batimastat (BB-94, 50 mg/kg) 1 h before and 24 h post-infection. Batimastat is suspended at 50 mg/mL in DMSO and stored frozen at -20°C. Prior to use, it is diluted 20-fold in phosphate buffered saline (PBS), and 500 μL are injected into animals. Control mice are injected with 500 μL of 5% DMSO in PBS. Animals are sacrificed 48 h after i.c. challenge. Rats[6] Female Sprague-Dawley rats are administered a single physiological dose of E2 (40 μg/kg in a 0.9% NaCl, 0.4% EtOH vehicle) by intraperitoneal (i.p.) injection at the indicated time intervals prior to tissue collection at necropsy. This in vivo dose level of E2 has been shown to induce changes in uterine wet weight, tissue architecture, and gene expression characteristic of estrogen receptor activation. For all other experiments, animals are i.p. administered a single 40 μg/kg bolus of E2 4 h prior to tissue harvest, while control animals receive vehicle only in all studies. Batimastat is administered i.p. at a dose level (40 mg/kg in a 1× PBS, 0.1% Tween-20 vehicle) shown to be effective at inhibiting MMPs in vivo 4 h prior to E2 or saline control. |
参考文献: [1]. Yin Z, et al. Increased MMPs expression and decreased contraction in the rat myometrium during pregnancy and in response to prolonged stretch and sex hormones. Am J Physiol Endocrinol Metab. 2012 Jul 1;303(1):E55-70. |
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