Metalloprotease inhibitors

Another PDF inhibitor series derived from comparisons with known metalloprotease inhibitor classes has been reported by Merck [68]. Their study investigated a small set of peptide aldehyde inhibitors, postulating that the aldehyde might bind to the metal centre in the form of a hydrate,... 

More recently, an additional approach to preventing TNF toxicity has been proposed. Several metalloprotease inhibitors (most notably hydroxamic acid) prevent proteolytic processing (i.e. release) of TNF-a from producer cell surfaces. Such inhibitors may also prove useful in preventing TNF-induced illness. The extent to which TNF (and inhibitors of TNF) will serve as future therapeutic agents remains to be determined by future clinical trials. 

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

Mercaptoacyl pharmacophore library. Zinc metalloproteases are inhibited by small molecules that contain mercaptans (thiols -CH2SH), carboxylic acids (-CO2H), and hydroxamic acids (-CONHOH). These functional groups chelate the active-site metal disrupting normal enzyme function. The angiotensinconverting enzyme (ACE) inhibitor Captopril is an example of a thiol-based metalloprotease inhibitor. Thiols, carboxylic acids, and hydroxamic acids are consequently affirmed pharmacophores for this protease family. A historical example of a pharmacophore-... 

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. 

In an early report on peptide hydroxamic acids as metalloprotease inhibitors, the peptide acid (Z-Gly-L-Leu-OH) was converted into the V-hydroxysuccinimide ester using DCC, which was subsequently reacted with hydroxylamineJ10 More reactive condensing reagents such as BOP can form the hydroxamic acid directly from the carboxylic acid and hydroxylamine via an intermediate HOBt ester. A number of hydroxamic acids has been synthesized by the treatment of the corresponding methyl esters with hydroxylamine in the presence of KOH 122 this reaction requires careful choice of reagent concentrations and ratios. In addition, the precursor carboxylic acid is treated with diazomethane to make the methyl ester. The use of diazomethane makes the procedure hazardous, but should be useful in special cases that require a better cost performance. 

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. 

Ishida K, Kato T, Murakami M, Watanabe M, Watanabe MF (2000) Microginins, Zinc Metalloproteases Inhibitors from the Cyanobacterium Microcystis aeruginosa. Tetrahedron 56 8643... 

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. 

Robl JA, Sun C-Q et al (1997) Dual metalloprotease inhibitors mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 40 1570-1577... 

In one of the steps in the synthesis of thienopyridine metalloprotease inhibitors possessing anticancer and antiinflammatory activities, the pyridine ring is constructed by treating (3-(2-thienyl)-D-alanine (274) with formaline in an acidic medium (1998EUP803505, 1999PCT9906410). In particular, this method was used to prepare 6-(R)-amino acid 275 in 91% yield. AT-Cbz-(3-(2-Thienyl)-L-alanine amide 276 was transformed into 4,5,6,7-tetrahydrothienopyridine-(65f)-carboxamide by dimeth-oxymethane in the presence of an acid (1996USP5480887). Compound 277 serves as an intermediate in the synthesis of anti-AIDS drugs. 

JA Robl, C Sun, J Stevenson, DE Ryono, LM Simpkins, MAP Cimarusti, T Dejneka, WA Slusarchyk, S Chao, L Stratton, RN Misra, MS Bednarz, MM Asaad, HS Cheung, BE Aboa-Offei, PL Smith, PD Mathers, M Fox, TR Schaeffer, AA Seymour, NC Trippodo. Dual metalloprotease inhibitors mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 40 1570-1577, 1997. 

Saito, S., Frank, G. D., Motley, E. D., et al. 2002. Metalloprotease inhibitor blocks angiotensin II-induced migration through inhibition of epidermal growth factor receptor transactivation. Biochem Biophys Res Commun 294 1023-1029. 

Metalloprotease Inhibitors. Relatively few irreversible inhibitors have been developed for metalloproteases (46). Some representative examples are given in Table IX. Most of the inhibitors are alkylating agents. 

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. 

Standard mechanism inhibitors are classified strictly as inhibitors of serine proteases. There have been reports of inhibitors of other classes of proteases that have similar mechanisms to those of standard mechanism inhibitors, though. Initial studies on the streptomyces metalloprotease inhibitor (SMPl) suggest that it inhibits the metalloprotease thermolysin through a substrate-like binding mechanism (2). Similarly, staphostatin B, a cysteine protease inhibitor from Staphylococcus aureus, binds in a substrate-like manner in the active site of staphopain cysteine proteases. However, staphostatin B has a glycine PI residue, which adopts a backbone conformation that seems to prevent nucleophilic attack of the scissiie bond (3). 

Wang J, Uttamchandani M, Sun LP, Yao SQ. Activity-based high-throughput profiling of metalloprotease inhibitors using small molecule microarrays. Chem. Commun. (Camb). 2006 (7) 717-719. 

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