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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Irreversible Inhibition of Serine Proteases – Design and In Vivo Activity of Diaryl α-Aminophosphonate Derivatives

Author(s): M. Sienczyk and J. Oleksyszyn

Volume 16, Issue 13, 2009

Page: [1673 - 1687] Pages: 15

DOI: 10.2174/092986709788186246

Price: $65


Diaryl esters of α-aminophosphonates are a group of low molecular weight inhibitors of serine proteases. For over 30 years these molecules have captured the attention of biochemists and medicinal chemists due to their similarity to the transition state of peptide bond cleavage observed in enzymatic reactions (transition state analogs) as well as their high potency of action. High reactivity toward serine proteases and complete lack of activity against cysteine or threonine proteases give α-aminophosphonates great advantage over other classes of inhibitors such as chloromethyl ketones or peptidyl derivatives of ketoesters and ketoamides, which are known to react with serine and cysteine proteases. Moreover, the selectivity of α-aminophosphonates action can be easily adjusted – even for serine proteases with similar specificity a small modification in the inhibitor structure could lead to absolute selectivity towards a particular enzyme. Furthermore α- aminophosphonate derivatives are successfully used as the activity based probes (ABP) for serine protease-like activity screening and as covalently reactive antigens for the development of catalytic antibodies (CAbs). The design of α-aminophosphonate diaryl ester inhibitors focuses on enzymes involved in the development and progression of pathophysiological states in living organisms. Examples include cancer growth and metastasis (urokinase-type plasminogen activator, uPA), diabetes or transplant rejection (dipeptidyl peptidase IV, DPPIV), osteoarthritis and lung injury (elastase) or heart failure (mast cell chymase). This review article focuses on the design of new α-aminophosphonic inhibitors as well as on in vivo studies performed previously using this class of inhibitors and includes recently published research data.

Keywords: Enzyme inhibitors, α-aminophosphonate diphenyl esters, serine proteases, activity based probes, catalytic antibodies

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