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Chemical Compound Review:

MMI270 (2R)-N-hydroxy-2-[(4- methoxyphenyl)sulfony...

Synonyms: CHEMBL267178, CGS-27023A, AC1L9JQY, DNC000955, DNC010718, ...

Prescott, M.F. et al., Moy, F.J. et al., Lee, P.P. et al., DiMicco, M.A. et al., Kopka, K. et al., et al.

Kopka, Breyholz, Wagner, Law, Riemann, Schröer, Trub, Guilbert, Levkau, Schober, Schäfers, Prescott, Sawyer, Von Linden-Reed, Jeune, Chou, Caplan, Jeng, Ganu, Melton, Wang, Roberts, DiMicco, Patwari, Siparsky, Kumar, Pratta, Lark, Kim, Grodzinsky, Yoshiizumi, Yamamoto, Miyasaka, Ito, Kumihara, Sawa, Kiyoi, Yamamoto, Nakajima, Hirayama, Kondo, Ishibushi, Ohmoto, Inoue, Yoshino, Eskens, Levitt, Sparreboom, Choi, Mather, Verweij, Harris,

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Disease relevance of CGS

The broad-spectrum MMP inhibitor CGS 27023A was tested to determine its potential as a therapy for atherosclerosis, aneurysm, and restenosis [1].
Oral administration of a matrix metalloproteinase inhibitor, CGS 27023A, protects the cartilage proteoglycan matrix in a partial meniscectomy model of osteoarthritis in rabbits [2].
Treatment with CGS 27023A (p.o., b.i.d. at 50 mg/kg) had no effect on the extent of aortic atherosclerosis (36 +/- 4% versus 30 +/- 2% in controls), but both aortic medial elastin destruction and ectasia grade were significantly reduced (38% and 36%, respectively, p < 0.05) [1].

Psychiatry related information on CGS

Therefore, radioiodinated analogues of the non-peptidyl broad-spectrum MMP inhibitor (MMPI) CGS 27023A 1a were synthesized for non-invasive detection of MMP activity in vivo using single photon emission computed tomography (SPECT) [3].

High impact information on CGS

The effects of medium supplementation with inhibitors of biosynthesis (cycloheximide), of matrix metalloproteinase (MMP) activity (CGS 27023A or GM 6001), and of aggrecanase activity (SB 703704) on GAG release after injury were assessed [4].
RESULTS: IL-1alpha stimulation of cartilage resulted in a fragmentation of COMP, which was inhibited by MMP inhibitors CGS 27023A and BB-94 [5].
Effect of food on the pharmacokinetics of oral MMI270B (CGS 27023A), a novel matrix metalloproteinase inhibitor [6].
Based on molecular weight, p-aminophenylmercuric acid activation, immunoblotting with MMP-specific antibodies, inhibition by EDTA, a peptide containing the prodomain sequence of MMP (TMRKPRCGNPDVAN) and two synthetic MMP inhibitors (BB-94 and CGS 27023A), these were classified as inactive and active forms of MMP-9 and MMP-2 [7].
Both the prodomain peptide (5 x 10(-4)-10(-3) M), as well as BB-94 (10(-8)-10(-5) M) and CGS 27023A (10(-6)-10(-5) M), inhibited TNF-induced proliferation and branching morphogenesis in a concentration-dependent manner [8].

Biological context of CGS

The hydroxamic acid moiety of CGS-27023A was found to chelate to the "right" of the catalytic zinc where the p-methoxyphenyl sits in the S1' active-site pocket, the isopropyl group is in contact with H83 and N80, and the pyridine ring is solvent exposed [9].
In the rat ballooned-carotid-artery model, CGS 27023A (12.5 mg/kg/day via osmotic minipump) reduced smooth muscle cell migration at 4 days by 83% (p < 0.001) [1].

Anatomical context of CGS

Matrix metalloproteinase inhibitor CGS 27023A protects COMP and proteoglycan in the bovine articular cartilage but not the release of their fragments from cartilage after prolonged stimulation in vitro with IL-1 alpha [10].

Associations of CGS with other chemical compounds

The solution structure of the catalytic fragment of human fibroblast collagenase (MMP-1) complexed with a sulfonamide derivative of a hydroxamic acid compound (CGS-27023A) has been determined using two-dimensional and three-dimensional heteronuclear NMR spectroscopy [9].

Gene context of CGS

Among the synthesized compounds, the ethoxyethoxy derivative 3o and the methoxypropoxy derivative 3p exhibited much more potent HB-EGF shedding inhibitory activity than CGS 27023A [11].

References

Effect of matrix metalloproteinase inhibition on progression of atherosclerosis and aneurysm in LDL receptor-deficient mice overexpressing MMP-3, MMP-12, and MMP-13 and on restenosis in rats after balloon injury. Prescott, M.F., Sawyer, W.K., Von Linden-Reed, J., Jeune, M., Chou, M., Caplan, S.L., Jeng, A.Y. Ann. N. Y. Acad. Sci. (1999) [Pubmed]
Oral administration of a matrix metalloproteinase inhibitor, CGS 27023A, protects the cartilage proteoglycan matrix in a partial meniscectomy model of osteoarthritis in rabbits. O'Byrne, E.M., Parker, D.T., Roberts, E.D., Goldberg, R.L., MacPherson, L.J., Blancuzzi, V., Wilson, D., Singh, H.N., Ludewig, R., Ganu, V.S. Inflamm. Res. (1995) [Pubmed]
Synthesis and preliminary biological evaluation of new radioiodinated MMP inhibitors for imaging MMP activity in vivo. Kopka, K., Breyholz, H.J., Wagner, S., Law, M.P., Riemann, B., Schröer, S., Trub, M., Guilbert, B., Levkau, B., Schober, O., Schäfers, M. Nucl. Med. Biol. (2004) [Pubmed]
Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury. DiMicco, M.A., Patwari, P., Siparsky, P.N., Kumar, S., Pratta, M.A., Lark, M.W., Kim, Y.J., Grodzinsky, A.J. Arthritis Rheum. (2004) [Pubmed]
Inhibition of interleukin-1alpha-induced cartilage oligomeric matrix protein degradation in bovine articular cartilage by matrix metalloproteinase inhibitors: potential role for matrix metalloproteinases in the generation of cartilage oligomeric matrix protein fragments in arthritic synovial fluid. Ganu, V., Goldberg, R., Peppard, J., Rediske, J., Melton, R., Hu, S.I., Wang, W., Duvander, C., Heinegård, D. Arthritis Rheum. (1998) [Pubmed]
Effect of food on the pharmacokinetics of oral MMI270B (CGS 27023A), a novel matrix metalloproteinase inhibitor. Eskens, F.A., Levitt, N.C., Sparreboom, A., Choi, L., Mather, R., Verweij, J., Harris, A.L. Clin. Cancer Res. (2000) [Pubmed]
Functional role of matrix metalloproteinases (MMPs) in mammary epithelial cell development. Lee, P.P., Hwang, J.J., Mead, L., Ip, M.M. J. Cell. Physiol. (2001) [Pubmed]
Functional significance of MMP-9 in tumor necrosis factor-induced proliferation and branching morphogenesis of mammary epithelial cells. Lee, P.P., Hwang, J.J., Murphy, G., Ip, M.M. Endocrinology (2000) [Pubmed]
NMR solution structure of the catalytic fragment of human fibroblast collagenase complexed with a sulfonamide derivative of a hydroxamic acid compound. Moy, F.J., Chanda, P.K., Chen, J.M., Cosmi, S., Edris, W., Skotnicki, J.S., Wilhelm, J., Powers, R. Biochemistry (1999) [Pubmed]
Matrix metalloproteinase inhibitor CGS 27023A protects COMP and proteoglycan in the bovine articular cartilage but not the release of their fragments from cartilage after prolonged stimulation in vitro with IL-1 alpha. Ganu, V., Melton, R., Wang, W., Roberts, D. Ann. N. Y. Acad. Sci. (1999) [Pubmed]
Synthesis and structure-activity relationships of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids as HB-EGF shedding inhibitors. Yoshiizumi, K., Yamamoto, M., Miyasaka, T., Ito, Y., Kumihara, H., Sawa, M., Kiyoi, T., Yamamoto, T., Nakajima, F., Hirayama, R., Kondo, H., Ishibushi, E., Ohmoto, H., Inoue, Y., Yoshino, K. Bioorg. Med. Chem. (2003) [Pubmed]

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