Design, synthesis and biological activity of novel peptidyl benzyl ketone FVIIa inhibitors

Publication: Research - peer-reviewJournal article – Annual report year: 2011

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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 Ki = 8 lM 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.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Publication date2011
Volume21
Pages3918-3922
ISSN0960-894X
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 0

Keywords

  • Serine protease inhibitor, C-Terminal modified peptide, Activated factor VII, Stabilization agent, Peptidyl benzyl ketone
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