Matrix metallo protease

Protease 3D structural models matrix metallo protease-inhibitor complexes... 

Very recently, (3-lactam antibiotics have been shown to offer neuroprotection by increasing glutamate transporters expression via gene activation [15] in addition, the discoveries of new biologically active (3-lactams such as cholesterol acyl transferase inhibitors [16-18], thrombin inhibitors [19], human cytomegalovirus protease inhibitors [20], matrix-metallo protease inhibitors [21], inhibitors of human leukocyte elastase (HLE) [22, 23] and cysteine protease [24, 25], and apoptosis inductors [26, 27] have provided much needed motivation for continuous development of new (3-lactam systems. 

Figure 1.12 The arylsulfonylhydroxamate scaffold (top) served as template structure for compounds active on various members of the matrix metallo-protease family, as well as of phosphodiesterase 4. By variation of the molecular periphery (R-groups, X top), discriminating compounds (bottom left, bottom middle), as well as dual inhibitors (bottom right) were obtained [61, 62].

ADAM. A Disintesrin And MetalloProteinase family of proteins. Disintegrins, as the name implies, are proteins which interfere with interactions of cells with proteins in the extracellular matrix. An example are the inhibitors of the interaction of blood platelets with fibrinogen. Disintegrins are found in snake venom. Metalloproteinases are a family of proteases which need a bivalent cation for catalysis. MMP s are matrix metallo-proteases. They are associated with the extracellular matrix. 

Table 3. Alignment of the sequences of the catalytic domain of selected human matrix metallo proteases (Matrixins). The sequences have been colored according to the secondary structure, with the zinc-chelating residues shown in white and the catalytic glutamic acid shown in red. Yellow residues identify amino acids discussed in the text.

Reported bioanalytical applications that use SS-LLE products include both tlie cartridge (tube) format and the microplate format. Some of these applications include the determination of mexiletine [44], amiodarone [45] and other antiarrhythmic drugs [46], proxyphylline [47], 16(3-hydroxystanozolol [48], dextromethorphan [49], and simvastatin [50] from biological fluids. Microplate applications for SS-LLE include a crude purification of crude combinatorial library samples [51], carboxylic acid-based matrix metallo-protease inhibitors [52], and a p3-adrenergic receptor agonist [53]. 

Banerjee, S., Bueso-Ramos, C., and Aggarwal, B.B. (2002) Suppression of 7,12-Dimethylbenz(a)anthracene-Induced Mammary Carcinogenesis in Rats by Resveratrol Role of Nuclear Factor-KB, Cyclooxygenase 2, and Matrix Metallo-protease 9, Cancer Res. 62,4945 954. 

Combinatorial chemists at Merck described the synthesis of a mechanism-based library (1.25) of matrix metallo-protease inhibitors combining both mix and split and indexed combinatorial techniques [10]. The results found in the study were consistent with the known SAR for this class of inhibitor. 

There are numerous examples of the application of rhodium and ruthenium catalysed hydrogenation of functionalised alkenes to the synthesis of pharmaceuticals. One such example is the hydrogenation of itaconate 3 in the synthesis of MMP-3 (Matrix Metallo Protease) inhibitor 5 (Scheme 14.3). Both rhodium and ruthenium catalysts were screened for the reduction of the free acid and carbojgrlate salts. It was found that rhodium catalysts performed well in the reduction of the free acid conversely the ruthenium catalysts were effective for the reduction of salts. Despite... 

---