Inhibitor, Matrix Metalloproteinase

Corbel M, Caulet-Maugendre S, Germain N, Molet S, Lagente V, Boichot E. Inhibition of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloproteinase inhibitor batimastat. J Pathol 2001 193(4) 538—545. 

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. 

Other agents such as actinomycin D, C-Myc antisense, dexamethasone, and matrix metalloproteinase inhibitors, aimed at altering inflammatory and smooth muscle actions in the biological repair response to vascular injury, are being evaluated. The success of these devices depends upon multiple issues, including stent platform, carrier, drug properties, and pharmacokinetic profile (18-26). Large randomized, controlled trials, demonstrate a restenosis rate of 5% to 10% with DES (27). 

Scheme 2.72 Assembly of matrix metalloproteinase inhibitors using supported...

Matter, H., Schudok, M., Schwab, W., Thorwart, W., Barrier, D., Billen, G., Haase, B., Neises, B., Weithmann, K., WOLLMANN, T. Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors design, synthesis and structure-activity relationship. Bioorg. Med. Chem. 2002, 10(11), 3529-3544. 

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.

Matter, H. and Schwab, W. Affinity and selectivity of matrix metalloproteinase inhibitors a chemometrical study from the perspective of ligands and proteins. 

Tetrahydroisoquinoline-3-carboxylate based matrix metalloproteinase inhibitors design, synthesis and structure-activity relationship. Bioorg. Med. Chem. 2002, 10, 3529-3544. 

Diguarher TL, ChoUet A-M, Bertrand M, et al. Stereospedfic synthesis of 5-substituted 2-bisarylthiocyclopentanecarboxyUcacid as specific matrix metalloproteinases inhibitors. J Med Chem 2003 46 3840-52. 

The ability of hydroxamic acids to act as bidentate ligands has made this functional group a key component in the design of most matrix metalloproteinase inhibitors. Due to its labile and diprotic nature, the hydroxamate is typically installed in its protected form at the end of the synthetic sequence. ... 

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

Wojtowicz PS, TorriJ, Johnson M, Steen V, Marshall J, Ness E, etal. Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J Clin Oncol 1998 16 2150-2156. 

Daniels R, Gupta E, Kollias G, Huang MQ, Patel RN, Manning J, et al. Safety and pharmacokinetics of BMS-275291, a novel matrix metalloproteinase inhibitor in health subjects. Proc Anna Meet Am Soc Clin Oncol 2001 (abstract) submitted. 

Tumor Models in Cancer Research, edited by Beverly A. Teicher, 2002 Tumor Suppressor Genes in Human Cancer, edited by David E. Fisher, 2001 Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J. Clendeninn and Krzysztof Appelt, 2001... 

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. 

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>. 

Opening of the dithiazole ring of the imidazolo[4,5-r7 [l,2,3]dithiazole 107 was employed as a key step in a multistep synthesis leading to hydroxamic acid derivatives 108 and 109 which are under investigation as matrix metalloproteinase inhibitors. Following initial reaction of 107 with NaOH treatment with 2-bromo-3-(4-chlorophenyl)propionic acid tert-butyl ester lead to the thioethers 108 from which 109 could be obtained (Scheme 10). <2000W0063197>. 

Structural Implications in the Design of Matrix-Metalloproteinase Inhibitors... 

Beckett RP, Davidson AH, Drummond AH, Huxley P, Whittaker M. Recent advances in matrix metalloproteinase inhibitor research. DDT 1996 1 16-26. 

The function of the often extravagant acyl substituent is also puzzling. The activity of the ancorinosides, e.g. (27), as membrane type 1 matrix metalloproteinase inhibitors does not seem to depend on the liposaccha-... 

Hajduk, P. J., et al., NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability. J Med Chem, 2002, 45, 5628-5639. 

AD Baxter, JB Bird, R Bannister, R Bhogal, DT Manallack, RW Watson, DA Owen, J Montana, J Henshilwood, RC Jackson. Matrix metalloproteinase inhibitors in cancer therapy. Totawa, NJ Humana Press, 2000, pp 193-222. 

Hidalgo M, Eckhardt SG, Development of matrix metalloproteinase inhibitors in cancer therapy, J Natl Cancer Inst, 2001 93(3) 178-193. 

Zempo N, Koyama N, Kenagy RD, et al. Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix metalloproteinase inhibitor, J Vase Biol 1996 16(I ) 28—33. 

Li CW, Cantor WJ, Robinson R, etal. Matrix metalloproteinase inhibitor GM600I selectively reduces intimal hyperplasia and intima collagen in stented but not balloon treated arteries. Can J Cardiol 2000 16(suppl F) I43E... 

Merck has used the L-phenylalanine-derived Evans oxazolidinone to make matrix metalloproteinase inhibitors such as 45 (Scheme 23.14) (see also Chapter 2).62 The mixed anhydride of 4-butyric acid was reacted with the lithium anion of the oxazolidinone. This was enolized with the standard titanium reagents. An enantioselective Michael addition was then carried out by the addition of t-butyl acrylate at low temperature. The auxiliary was removed with LiOH/peroxides to give the acid, which was further derivatized over multiple steps to yield the desired drug. 

Whittaker M, Floyd CD, Brown P et al (1999) Design and therapeutic application of matrix metalloproteinase inhibitors. Chem Rev 99 2735-2776... 

Skiles JW, Gonnella NC, Jeng AY (2001) The design, structure, and therapeutic application of matrix metalloproteinase inhibitors. Curr Med Chem 8 425-474... 

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