A series of derivatives of 2,4- and 2,5-thiazolyl- or oxazolylbenzenesulphonamides has been prepared and evaluated as potential MMP inhibitors. The thiazole 15b have been found to exhibit MMP-2 and MMP-9 inhibitions higher than reference compounds GI 129471 and CGS 27023A.

01 Apr 2002·Experimental Cell ResearchQ3 · MEDICINE

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Q3 · MEDICINE

Article

Author: Carine Munaut ; Charles Lambert ; Francis Frankenne ; Erik Maquoi ; Jean-Michel Foidart ; Alain Colige ; Hans-Willi Krell ; Frank Grams ; Agnès Noël

Enhanced expression and activation of matrix metalloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the proteolytic activity of these enzymes recently emerged as a potential therapeutic tool to treat cancer. In this study, we report that GI129471, a synthetic broad-spectrum MMP inhibitor, efficiently reduced the in vitro invasiveness of HT1080 cells through type IV collagen, a major component of basement membranes. This reduced invasion was paralleled by a complete inhibition of pro-MMP-2 activation; however, GI129471 strongly increased the amount of secreted pro-MMP-9, which could be subsequently activated through a plasminogen-dependent mechanism. Quantitative RT-PCR and northern blot analysis revealed that GI129471 specifically increased the MMP-9 mRNA steady-state level. Moreover, transient transfection of HT1080 cells with beta-galactosidase reporter vectors containing different lengths of the 5'-flanking region of the MMP-9 gene revealed an upregulation of the transcriptional activity of the corresponding promoter. Well-known modulators of MMP-9 expression such as Il-1beta and TNF-alpha were not involved in this upregulation. These findings emphasize the complexity of the regulation of MMP expression and the requirement for a detailed characterization of the potential adverse side effects associated with the use of broad-spectrum MMPIs.

01 Nov 2001·ImmunologyQ3 · MEDICINE

Rat mast cell protease‐I enhances immunoglobulin E production by mouse B cells stimulated with interleukin‐4

Q3 · MEDICINE

Article

Author: Koji Naito ; Tsutomu Yoshikawa ; Norifumi Nakamura ; Hiroshi Nakakubo ; Teruaki Imada

SummaryMast cell chymase plays important roles in inflammation and tissue remodeling. Here we show that mast cell chymase also functions as an enhancer of immunoglobulin production. In the culture of murine spleen cells stimulated with lipopolysaccharide and interleukin‐4, purified rat chymase (rat mast cell protease‐I; RMCP‐I), at physiological concentrations, enhanced immunoglobulin E (IgE) and IgG1 syntheses but not IgG3 synthesis. The enhancement was also evident when spleen cells depleted of T cells and macrophages were employed as responding cells. Enzymatic activity of RMCP‐I was required to enhance IgE and IgG1, because two inhibitors for chymotryptic enzymes, chymostatin and Y‐40613, a novel chymase inhibitor, suppressed the enhanced immunoglobulin production, and phenylmethylsulphonyl fluoride, an irreversible inhibitor for serine proteases, totally abolished the enhancing effect. Furthermore, a specific inhibitor for Zn2+‐dependent metalloproteases, GI 129471, could also completely inhibit the production of IgE and IgG1 that was enhanced by RMCP‐I, suggesting that a metalloprotease also played an essential role in the immunoglobulin production. Our results together with others show that proteases from mast cell granules have important function not only in the efferent phase but also in the afferent phase of immune responses.

100 Deals associated with GI-129471

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Discovery	US	Glaxo Group Ltd.	-
Rheumatoid Arthritis	Discovery	US	Glaxo Group Ltd.	-

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