Substrate Related O,O-Dialkyldipeptidylaminophosphonates, A New Type of Thrombin Inhibitor

Abstract

The facile reduction of O,O-dialkyl 1-hydroxyiminoalkanephosphonate precursors, using LiBH₄/Me₃SiCl in THF at ambient temperature, conveniently affords O,O-dialkyl 1-aminoalkanephosphonates in good yield and high state of purity. O,O-Dialkyl 1-aminobenzylphosphonates may be prepared in high yield and purity from catalytic hydrogenolysis of their 1-benzylaminobenzylphosphonate precursors. These biologically active aminophosphonates, when coupled to substrate derived dipeptides, produced a range of novel phosphonotripeptides based upon the ‘fibrinogen-like’ sequence H-D-Phe-Pro-Arg; where the phosphorus structural units replace the ‘Pl’Arg. These tripeptides showed a marked inhibitory specificity towards the trypsin-like serine protease thrombin, a ubiquitous enzyme that plays a crucial role in the cardiovascular system. The compounds possess an initial K_i in-vitro in the micromolar range against thrombin. Further enzyme kinetic analysis of the compound Z-D-Dpa-Pro-Pgl^P(OiPr)₂ (IC₅₀ 11.7 micromolar), showed that it displayed competitive inhibition characteristics toward thrombin, in contrast to the two stage slow-tight binding kinetics that had been shown by the analogous O,O-diphenyl derivative.

Key Words::

• Aminophosphonates
• phosphonotripeptides
• thrombin inhibition
• antithrombotic agents