New N alpha-guanidinobenzoyl derivatives of hirudin-54-65 containing stabilized carboxyl or phosphoryl groups on the side chain of phenylalanine-63.
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.
Thurieau
C
C
Department of Peptide Chemistry, Institut de Recherches Servier, Suresnes, France.
Simonet
S
S
Paladino
J
J
Prost
J F
JF
Verbeuren
T
T
Fauchère
J L
JL
D000595:Amino Acid Sequence; D000818:Animals; D004355:Drug Stability; D005340:Fibrinogen / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D006629:Hirudins / Q000737:chemistry*; D006868:Hydrolysis; D007700:Kinetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010649:Phenylalanine / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D006146:Guanidines; D006629:Hirudins; D010446:Peptide Fragments; D010649:Phenylalanine; D005340:Fibrinogen; D013917:Thrombin