Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors: design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex.
A morpholinone structural motif derived from D(+)- and L(-)-malic acid has been used as a mimic of D-Phe-Pro in the thrombin inhibiting tripeptide D-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the alpha-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC(50) of 720 nM. The X-ray crystal structure of this candidate co-crystallized with alpha-thrombin is discussed.
Dahlgren
Anders
A
Department of Chemistry, Linköping University, S-581 83, Linköping, Sweden.
Johansson
Per Ola
PO
Kvarnström
Ingemar
I
Musil
Djordje
D
Nilsson
Ingemar
I
Samuelsson
Bertil
B
D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009025:Morpholines / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D009025:Morpholines; D009842:Oligopeptides; C077952:phenylalanyl-prolyl-arginine; D013917:Thrombin