Journal
CURRENT MEDICINAL CHEMISTRY
Volume 16, Issue 13, Pages 1673-1687Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/092986709788186246
Keywords
Enzyme inhibitors; alpha-aminophosphonate diphenyl esters; serine proteases; activity based probes; catalytic antibodies
Funding
- State Committee for Scientific Research [N405 342633]
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Diaryl esters of alpha-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 alpha-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 alpha-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 alpha-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 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 alpha-aminophosphonic inhibitors as well as on in vivo studies performed previously using this class of inhibitors and includes recently published research data.
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