New- Nα-Guanidinobenzoyl Derivatives of Hirudin-54-65 Containing Stabilized Carboxyl or Phosphoryl Groups on the Side Chain of Phenylalanine-63

Article abstract of DOI:10.1021/jm00031a012

We report on the synthesis and pharmacological properties of a new series of thrombin inhibitors derived from hirudin carboxyl-terminal fragments.Two (arylphosphono)phenylalanines, p-PO3H2-L-Phe¹ and m-PO3H2-L-Tyr, and one (carboxymethyl)phenylalanine, p-CH2COOH-L-Phe, were prepared and incorporated into position 63 of the modified hirudin's C-terminal dodecapeptide using the Fmoc solid-phase synthesis strategy.Substitution by any one of the residues led to very active analogs which doubled the thrombin time at low micromolar concentration (C_tt2) in vitro (1 μM < Ctt₂ < 3 μM) and potently increased the activated partial thromboplastin time (APTT) ex vivo.These compounds displayed a higher potency in vitro and a longer duration of action in vivo than both the corresponding sulfated or phosphorylated tyrosine counterparts.