Synthesis of Novel Thrombin Inhibitors. Use of Ring-Closing Metathesis Reactions for Synthesis of P2 Cyclopentene and Cyclohexene Dicarboxylic Acid Derivatives
2003 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 7, 1165-1179 p.Article in journal (Refereed) Published
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 α-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 IC50 of 49 nM.
Place, publisher, year, edition, pages
2003. Vol. 46, no 7, 1165-1179 p.
IdentifiersURN: urn:nbn:se:liu:diva-13468DOI: 10.1021/jm021065aOAI: oai:DiVA.org:liu-13468DiVA: diva2:20822