title: Design, synthesis and biological activity of novel peptidyl benzyl ketone FVIIa inhibitors.
abstract: Herein is described the synthesis of a novel class of peptidyl FVIIa inhibitors having a C-terminal benzyl ketone group. This class is designed to be potentially suitable as stabilization agents of liquid formulations of rFVIIa, which is a serine protease used for the treatment of hemophilia A and B inhibitor patients. A library of compounds was synthesized with different tripeptide sequences, N-terminals and d-amino acids in the P3 position. Cbz-D-Phe-Phe-Arg-bk (33) was found to be the best candidate with a potency of K(i)=8μM and no substantial inhibition of related blood coagulation factors (thrombin and FXa). Computational studies revealed that 33 has a very stable binding conformation due to intramolecular hydrogen bonds, which cannot be formed with l-Phe in the P3 position. Nonpolar amino acids were found to be superior, probably due to a minimization of the cost of desolvation upon binding to FVIIa.
authors.affiliation: Technical University of Denmark, Department of Chemistry, Kemitorvet, Building 201, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Storgaard
authors.forename: Signe T
authors.initials: ST
authors.lastname: Henriksen
authors.forename: Florencio
authors.initials: F
authors.lastname: Zaragoza
authors.forename: Bernd
authors.initials: B
authors.lastname: Peschke
authors.forename: David
authors.initials: D
authors.lastname: Tanner
mesh_terms: D001667:Binding, Competitive; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000235:genetics; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D007659:Ketones; D009842:Oligopeptides; D010455:Peptides; D011994:Recombinant Proteins; C562361:benzyloxycarbonyl-phenylalanyl-phenylalanyl-arginine benzyl ketone; C103587:recombinant FVIIa; D015942:Factor VIIa