Journal article
Design, synthesis and biological activity of novel peptidyl benzyl ketone FVIIa inhibitors
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.
Language: | English |
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Year: | 2011 |
Pages: | 3918-3922 |
ISSN: | 14643405 and 0960894x |
Types: | Journal article |
DOI: | 10.1016/j.bmcl.2011.05.025 |
ORCIDs: | Tanner, David Ackland |