Synthesis of novel thrombin inhibitors. Use of ring-closing metathesis reactions for synthesis of P2 cyclopentene- and cyclohexenedicarboxylic acid derivatives.
The thrombin inhibitory tripeptide d-Phe-Pro-Arg has been mimicked using either cyclopentenedicarboxylic derivatives or a cyclohexenedicarboxylic derivative as surrogate for the P2 proline. In the P3 position, tertiary amides were optimized as d-Phe P3 replacements. The P1 arginine was, in all compounds, substituted with the more rigid and biocompatible 4-aminomethylbenzamidine. One of the novel inhibitors was cocrystallized with alpha-thrombin and subjected to X-ray analysis. From analysis of the X-ray crystal structure, new ligands were designed leading to significantly improved binding affinity, the lead candidate exhibiting an in vitro IC(50) of 49 nM.
Thorstensson
Fredrik
F
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
Kvarnström
Ingemar
I
Musil
Djordje
D
Nilsson
Ingemar
I
Samuelsson
Bertil
B
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000577:Amides; D001549:Benzamides; D003510:Cyclohexanes; D003517:Cyclopentanes; D003998:Dicarboxylic Acids; D008024:Ligands; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; C473480:cyclopent-2-ene-1,2-dicarboxylic acid 1-(4-carbamimidoylbenzylamide) 2-(cyclohexyl(2,5-dimethoxyphenyl)amide); C077952:phenylalanyl-prolyl-arginine; D013917:Thrombin