title: New N alpha-guanidinobenzoyl derivatives of hirudin-54-65 containing stabilized carboxyl or phosphoryl groups on the side chain of phenylalanine-63.
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.
authors.affiliation: Department of Peptide Chemistry, Institut de Recherches Servier, Suresnes, France.
authors.forename: C
authors.initials: C
authors.lastname: Thurieau
authors.forename: S
authors.initials: S
authors.lastname: Simonet
authors.forename: J
authors.initials: J
authors.lastname: Paladino
authors.forename: J F
authors.initials: JF
authors.lastname: Prost
authors.forename: T
authors.initials: T
authors.lastname: Verbeuren
authors.forename: J L
authors.initials: JL
authors.lastname: Fauchère
mesh_terms: 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
chemical_list: D006146:Guanidines; D006629:Hirudins; D010446:Peptide Fragments; D010649:Phenylalanine; D005340:Fibrinogen; D013917:Thrombin