Matrix metalloprotease inhibitors

Heath EI, Grochow LB. Qinical potential of matrix metalloprotease inhibitors in cancer therapy. Drugs 2000 59 1043-55. 

Lynas, J. F., Martin, S. L., Walker, B., Baxter, A. D., Bird, J., Bhogal, R., Montana, J. G., Owen, D. A. (2000) Solid-phase synthesis and biological screening of N-a-mercaptoamide template-based matrix metalloprotease inhibitors. Comb Chem High Throughput Screening 3, 37—41. 

Many successful matrix metalloprotease inhibitors include various succinyl moieties attached to the hydroxamic acid function. During the synthesis, a number of intermediates were prepared and are shown in Schemes 4-8. The synthesis of actinonin 6 begins by reaction of pentylmaleic anhydride with O- benzylhydroxylamine (Scheme 4). The product... 

In order to add more diversity to the succinyl moiety, another asymmetric carbon can be introduced, e.g. formation of 18 (Scheme 8). The second chiral center is created by using methyl, (arylsulfanyl)methyl, morpholinomethyl, and hydroxy groups. The typical matrix metalloprotease inhibitors are shown in Scheme 2. 

M. Whittaker, C. D. Floyd, P. Brown and A. J. H. Gearing, Design and therapeutic application of matrix metalloprotease inhibitors, Chem. Rev. 1999, 99, 2735-2776. 

The explosion of science in the latter half of the 20th century, elueidating eomponents of the adhesion complex between the epithelial and stromal layers of the cornea, suggest the basement membrane zone may become a target area for therapy in the future. Indeed, protease inhibitors of enzymes that remodel the basement membrane show promise as eountermeasures. Using rabbits for an ocular SM vapor challenge, the matrix metalloprotease inhibitors... 

Galardy, R., Grohelny, D., Foellmer, H., Fernandez, L. (1994). Inhibition of angiogenesis by the matrix metalloprotease inhibitor N-[2R-2-(hydroxamidocarbonymethyl)-4-methyl-pentanoyl)]-L-tryptophan methylamide. Cancer Res. 54 4715-18. 

Doxycycline inhibits the detachment of SM-exposed HaCaT cells in culture from the growth substrate. However, analysis of the metabolic activity of the adherent cells reveals that doxycycline treatment does not maintain cell viability. It is suggested that doxycycline and other matrix metalloprotease inhibitors may have a role to play in therapeutic intervention against SM, only as a combination therapy (Lindsay et al, 2007). Human keratinocyte cell lines were pretreated with mixtures of methenamine and glutathione prior to SM exposure. Though it is possible to protect the cell cultures from the toxic effects of SM, it will be effective only as a pretreatment (Smith et al, 1997). 

J. W. Skiles, N. C. Gonnella, A. Y. Jeng, The Design, Structure, and Therapeutic Application of Matrix Metalloprotease Inhibitors, Curr. Med. Chem. 2001, 8, 425-474. 

VS Patel, ME Dowty, TR Baker, SX Peng, MJ Janusz, YO Taiwo. Utilization of N-in-one and in vivo efficacy data for matrix metalloprotease inhibitors to optimize the compound selection process PharmSci 1, 1998. 

Garcia C, Bartsch DU, Rivero ME, et al. Efficacy of Prinomastat (AG3340), a matrix metalloprotease inhibitor, in treatment of retinal neovascularization. Curr Eye Res 2002 24 33-38. 

Matter, H. and Schudok, M. (2004) Recent advances in the design of matrix metalloprotease inhibitors. Current Opinion in Drug Discovery S, Development, 7, 513-535. 

Blocking metabolism needn t always involve direct replacement of an atom at the metabolic site. Electronic effects from substituents at other positions can sometimes do the trick as well. For example, pnra-hydroxylation of a benzene ring can sometimes be curtailed by meta.meta-difluorination. If changing the electronics of a molecule can work, it s a cinch that chemists will try using steric effects as well. The improved rat PK properties of Compound 23, the matrix metalloprotease inhibitor shown in Figure 9.24 (Clp 44 mL min kg ), versus Compound 2, which lacks the a,a-dimethyl group (Clp 86 mL min kg ) were attributed in part to steric hindrance of metabolism of the hydroxamic acid. ... 

R 303 B. Bluemich, S. Anferova, F. Casanova, K. Kremer, J. Perlo and S. Sharma, Unilateral NMR Principles and Applications to Quality Control of Elastomer Products , KGK, Kaut.Gummi Kunstst., 2004,57,346 R 304 PJ. Bond and M.S. Sansom, The Simulation Approach to Bacterial Outer Membrane Proteins (Review) , Mol.Membr.Biol., 2004,21,151 R 305 N. Borkakoti, Matrix Metalloprotease Inhibitors Design from Structure , Biochem.Soc.Trans., 2004,32,17... 

USE Matrix metalloprotease inhibitors and their application in cosmetic and pharmaceutical compositions [6868],... 

Bluhm H, Hochgiirtel M, Kroth H, Essers M, Gege C, Richter F, Taveras A (2008) Heterobicyclic matrix metalloprotease inhibitors. WO/2008/063669... 

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