TY - JOUR
T1 - Design, synthesis and biological activity of novel peptidyl benzyl ketone FVIIa inhibitors
AU - Storgaard, Morten
AU - Henriksen, Signe Teuber
AU - Zaragoza, Florencio
AU - Peschke, Bernd
AU - Tanner, David Ackland
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Serine protease inhibitor
KW - C-Terminal modified peptide
KW - Activated factor VII
KW - Stabilization agent
KW - Peptidyl benzyl ketone
U2 - 10.1016/j.bmcl.2011.05.025
DO - 10.1016/j.bmcl.2011.05.025
M3 - Journal article
C2 - 21641796
SN - 0960-894X
VL - 21
SP - 3918
EP - 3922
JO - Bioorganic & Medicinal Chemistry Letters
JF - Bioorganic & Medicinal Chemistry Letters
ER -