α-Aminoalkylphosphonates as a tool in experimental optimisation of P1 side chain shape of potential inhibitors in S1 pocket of leucine- and neutral aminopeptidases

• Published in: European journal of medicinal chemistry 2005-08, Vol.40 (8), p.764-771
• Main Authors: Drąg, Marcin, Grembecka, Jolanta, Pawełczak, Małgorzata, Kafarski, Paweł
• Format: Article
• Language: English
• Subjects: Aminopeptidase N; Aminopeptidases - antagonists & inhibitors; Aminopeptidases - chemistry; Aminophosphonates; Analytical, structural and metabolic biochemistry; Animals; Binding Sites - drug effects; Biological and medical sciences; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydrogen-Ion Concentration; Hydrolases; Inhibitor; Kidney - enzymology; Leucine - chemistry; Leucine aminopeptidase; Leucyl Aminopeptidase - antagonists & inhibitors; Leucyl Aminopeptidase - chemistry; Molecular Structure; Organophosphonates - chemistry; Organophosphonates - pharmacology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2005.02.011

The synthesis and biological activity studies of the series of structurally different α-aminoalkylphosphonates were performed in order to optimise the shape of the side chain of the potential inhibitors in S1 pocket of leucine aminopeptidase [E.C.3.4.11.1]. Analysis of a series of compounds with aromatic, aliphatic and alicyclic P1 side chains enabled to find out the structural features, optimal for that fragment of inhibitors of LAP. The most active among all investigated compounds were the phosphonic analogues of homo-tyrosine ( K i = 120 nM) and homo-phenylalanine ( K i = 140 nM), which even as racemic mixtures were better inhibitors in comparison with the best till now-phosphonic analogue of l-leucine (230 nM). Additional comparison of the inhibitory activity obtained for aminopeptidase N (APN, E.C.3.4.11.2) give insight into structural preferences of both enzymes.