Matrix metalloproteinase inhibitors, for

Maximizing the Therapeutic Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Cancer... 

S. Furumoto, R. Iwata, T. Ido, Design and synthesis of fluorine-18 labeled matrix metalloproteinase inhibitors for cancer imaging, J. Label. Compd. Radiopharm. 45 (2002) 975-986. 

DiJoseph, J. F., Sung, A., Sharr, M. A., Killar, L. M., Walter, T., Jin, G., Cowling, R., Tillett, J., Zhao, W., McDevitt, J., Xu, Z. B. Synthesis and structure-activity relationship of A-substituted 4-aryl-sulfonylpiperidine-4-hydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. J. Med. Chem. 2003, 46(12), 2376-2396. 

The 3-carboxamido derivatives of pyrimido[6,l-c][l,4]oxazine-6,8-diones 164 (Y = 0), as with their nitrogen and sulfur-containing analogues, are matrix metalloproteinase inhibitors useful for treating MMP-13 enzyme-mediated diseases (e.g., heart failure, multiple sclerosis, and macular degeneration) <2004W02004/014354>. 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

Fig. 14.12 VolSurf model to correlate 49 matrix metalloproteinase inhibitors with different zinc-binding functionalities to rabbit oral bioavailability for metabolically stable compounds. (A) Semiquantitative PLS model 0.424, r 0.646, 4 PLS components) to rank novel synthesis candidates. Main factors influencing absorption, that is, lower polarity, capacity factors and increased hydrophobicity, are in agreement with global models for human intestinal absorption. (B) Distribution of polar and hydrophobic surfaces for two molecules with low (0981) and higher (2290) rabbit AUC from oral pharmacokinetic studies.

The most straightforward method for the synthesis of the sulfonamide class of 1,2-thiazines is the intramolecular amidation reaction between a sulfonyl chloride and an amine. Preparation of the sulfonyl chloride moiety via the oxidation of thiol acetate 179 and subsequent deprotection and cyclization afforded sulfonamide 180, an intermediate for the synthesis of the matrix metalloproteinase inhibitor 38 (Scheme 22) <2004JME2981>. 

Other reported zinc binding chelators used in matrix metalloproteinase inhibitors are summarized in Fig. 15.26. For instance, one of the oxygens in the phosphonamide (57) binds strongly to the zinc ion, whereas the other one coordinates weakly with the metal (110). More recently, suicide substrate MMP inhibitors have appeared (58)(Fig. 15.26) (111). The se-... 

The use of enzymes to stereospecifically form amide bonds has been described in many texts (115) however, the commercial availability cf cross-linked enzyme crystals (CLECs), for example, PeptiCLEC-TR, which is an immobilized form of Thermolysin protease, has been used in the synthesis of D2163 (68), a novel matrix metalloproteinase inhibitor (116). In vitro enzyme screening identified the all-natural SSS-isomer as the active product. The elegant CLEC (117) technology used in this example makes the enzyme stable to typical organic reaction conditions and enables facile removal of the enzyme at the end of the reaction by simple filtration. On this basis, it is... 

Hu, J., Van den Steen, P. E., Sang, Q.-X. A. and Opdenakker, G. (2007) Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nature Reviews Drug Discovery, 6, 480-498. 

Gum RJ, Hickman D, Fagerland JA, Heindel MA, Gagne GD, Schmidt JM, et al. Analysis of two matrix metalloproteinase inhibitors and their metabolites for induction of phospholipidosis in rat and human hepatocytes. Biochem Pharmacol 2001 62 1661-73. 

Buchardt, J. Schiodt, C.B. Krog-Jensen, C. Delaisse, J-M. Foged, N.T. Meldal, M. Solid Phase Combinatorial Library of Phosphinic Peptides for Discovery of Matrix Metalloproteinase Inhibitors, J. Comb. Chem. 2,624-638 (2000). 

The THP-based hnker can be modified in such a way as to allow fhe synthesis of hydroxamic acids 49, as outlined in Scheme 24. Linker 48 has played a role in the solid-phase synfhesis of matrix metalloproteinase inhibitors [52], Alternative linkers that yield hydroxamic acids after release have been used in connection with peptide chemistry, as well as for the preparation of combinatorial compounds [53-58]. 

Finally, for patients interested in chnical trials, investigational strategies with oral doxycychne, matrix metalloproteinase inhibitors. 

Figure 6.19 values of fragments tested for their ability to chelate the active site zinc in stromelysin as determined by NMR. (Hajduk, PJ. et al. NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability. J. Med. Chem. 2002, 45, 5628-5639.)... 

For a synthesis of Hoffmann-La Roche s matrix metalloproteinase inhibitor trocade (Ro32-3555) Hilpert, H. 

Sugimoto A., Fukuyama T., Rahman M., Ryu I. An automated-flow microreactor system for quick optimization and productiomapplication of 10-and 100-gram order productions of a matrix metalloproteinase inhibitor using a Sonogashira coupling reaction. Tetrahedron Lett. 2009 50 (46) 6364-6367. 

Fig. 3 The SAR by NMR approach. Example of a small bidentate molecule designed using this approach. The example shown is for the design of a potent inhibitors of the matrix metalloproteinase MMP3. (a) Docked structures of the identified fragment leads are shown with cyan carbons, whereas the linked compound is shown with green carbon atoms. All structures were experimentally determined by NMR. (b) Chemical structures (and in vitro potencies) of the fragment leads and subsequent high-affinity linked compounds. Adapted from [7]...

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