New N alpha-guanidinobenzoyl derivatives of hirudin-54-65 containing stabilized carboxyl or phosphoryl groups on the side chain of phenylalanine-63
Research article published in Journal of medicinal chemistry (1994)
Abstract
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 (Ctt2) in vitro (1 microM < Ctt2 < 3 microM) 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.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Summary
New N alpha-guanidinobenzoyl derivatives of hirudin-54-65 containing stabilized carboxyl or phosphoryl groups on the side chain of phenylalanine-63.
Why This Matters for Hirudotherapy
This study reports the synthesis and pharmacological properties of a new series of thrombin inhibitors derived from hirudin carboxyl-terminal fragments, incorporating one of three residues—p-PO3H2-L-Phe, m-PO3H2-L-Tyr, or p-CH2COOH-L-Phe—at position 63 of the modified hirudin C-terminal dodecapeptide via Fmoc solid-phase synthesis. The resulting analogs doubled thrombin time at low micromolar concentrations (1 µM < Ctt2 < 3 µM) in vitro, potently increased activated partial thromboplastin time ex vivo, and displayed higher in-vitro potency and longer in-vivo duration than the corresponding sulfated or phosphorylated tyrosine counterparts. Because these are hirudin-derived analogs, the work has a defensible—if indirect—connection to leech-derived anticoagulants; however, the abstract evaluates chemically synthesized fragments rather than natural leech secretions or live hirudotherapy.
Citation
New N alpha-guanidinobenzoyl derivatives of hirudin-54-65 containing stabilized carboxyl or phosphoryl groups on the side chain of phenylalanine-63
Thurieau C et al. · Journal of medicinal chemistry, 1994
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