Enzyme-activated irreversible inhibitors

I.A. McDonald, J.M. Lacoste, P. Bey, M.G. Palfreyman, M. Zreika, Enzyme-activated irreversible inhibitors of monoamine oxidase Phenylallylamine stmcture-activity relationships, J. Med. Chem. 28 (1985) 186-193. 

The but-3-ynoic acid moiety which is present in this isostere may constitute the reactive part in enzyme-activated irreversible inhibitors. 130 ... 

R. H. Abeles, in Enzyme-activated irreversible inhibitors (N. Seiler, M. J. Jung, and J. Koch-Weser, Eds.), Elsevier North-Holland, p. 4 (1978). 

Active-Site-Directed and Enzyme-Activated Irreversible Inhibitors Affinity Labels and Suicide Inhibitors ... 

There are two types of inhibitors. Reversible inhibitors bind to an enzyme in a reversible fashion and can be removed by dialysis (or dilution) to restore full enzyme activity. Irreversible inhibitors cannot be removed by dialysis and, in effect, permanently deactivate or denature the enzyme. 

Substituted benzylsilylmethylamines have been synthetized88,489,490 and tested on rat brain MAO as potent and selective (MAO-B versus MAO-A) enzyme activated irreversible inhibitors of rat brain MAO-B in vitro.490 491... 

Figures 4,6, and 7 have been reproduced from B. W. Metcalf et al., "Enzyme activated irreversible inhibition of transaminases" in "Enzyme-Activated Irreversible Inhibitors,"...

Seiler, N. Jung, M.J. Koch-Weser, J., eds., "Enzyme-Activated Irreversible Inhibitors," 1978, Elsevier/North Holland Biomedical Press. 

A final group of covalent small-molecule inhibitors of proteases are mechanism-based inhibitors. These inhibitors are enzyme-activated irreversible inhibitors, and they involve a two-hif mechanism that completely inhibits the protease. Some isocoumarins and -lactam derivatives have been shown to be mechanistic inhibitors of serine proteases. A classic example is the inhibition of elastase by several cephalosporin derivatives developed at Merck (Fig. 8). The catalytic serine attacks and opens the -lactam ring of the cephalosporin, which through various isomerization steps, allows for a Michael addition to the active site histidine and the formation of a stable enzyme-inhibitor complex (34). These mechanism-based inhibitors require an initial acylation event to take place before the irreversible inhibitory event. In this way, these small molecules have an analogous mechanism of inhibition to the naturally occurring serpins and a-2-macroglobin, which also act as suicide substrates. 

Further work on the 7a-(4 -aminophenyl)thioandrostenedione (61, 7-APTA) was undertaken. The synthesis of an unsaturated derivative of (61) has resulted in the conversion of a reversible competitive inhibitor of AR into an enzyme-activated irreversible inhibitor. 7a-(4 -Aminophenyl)thio-l,4-androstadiene-3,17-dione (62, 7-APTADD) has an apparent Ki value of 9.9 + 1.0 nM (.Sfn, for androstenedione of 52.5 + 5.9 nM) and demonstrated rapid... 

Covey, D.G., W.F. Hood, and VD. Parikh (1981). I Op-Propynyl-substituted steroids Mechanism-based enzyme-activated irreversible inhibitors of estrogen biosynthesis. v< Biol. Chem. 256, 1076-1079. 

Seiler N, Jung MJ, Kock-Weser J, eds. Enzyme-Activated Irreversible Inhibitors. New York Elsevier North Holland, 1978. 

Seiler, N., Jung, M. and Koch-Weser, E. (eds) (1978) Enzyme-Activated Irreversible Inhibitors, Amsterdam Elsevier. 

The synthesis of allylamines and corresponding a-amino-acids as inhibitors of clinically relevant enzymes has been reported. Seventeen 2-aryl-3-haloallylamine derivatives were prepared and evaluated as potential monoamine oxidase inhibitors, and found to be enzyme-activated irreversible inhibitors whose selectivity for... 

Covey DG, Hood WF, Parikh VD (1981) lOP-Propynyl-substituted steroids mechanism-based enzyme-activated irreversible inhibitors of estrogen biosynthesis. J Biol Chem 256 1076-1079... 

Suicide Substrates. Much like affinity labels, suicide inhibitors first form a reversible complex with the target enzyme due to the structural similarity between inhibitor and substrate. In a subsequent time dependent step, an irreversible complex (usually covalent) is formed with an appropriately positioned amino acid side chain. Unlike the affinity label, suicide substrates (65) are not inherently reactive and must undergo activation by the target enzyme before the irreversible complex is formed. Therefore, these inhibitors are generally more selective than affinity labels. Since the enzyine catalyzes its own inactivation, these inhibitors are also known as kcat inhibitors (66), enzyme-activated, irreversible inhibitors (54) and Trojan horse reagents (6. ... 

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