Design of a novel class of bifunctional thrombin inhibitors, synthesised by the first application of peptide boronates in solid phase chemistry

Borologs containing peptide boronates are new bifunctional biologically active molecules which bind to and inhibit thrombin. These compounds are designed based on the C-terminal sequence of hirudin. The inhibitors consists of four parts, i) an active site inhibitor, D-Phe Pro-Boro(aa)-OPin. ii) an anion binding exosite association moiety, Hirudin, iii) a spacer to link these components and iv) a novel 'flexor' non-peptide unit to allow correct orientation. The bivalent nature of the inhibitor [-D-PheProBoroBpgOPin]CO(CH2)(3)COGly(2)Hir enhanced binding up to 10 fold greater than the corresponding native peptide Z-D-PheProBoroBpgOPin or the mixture of non covalently linked units, and resulted in a potent and selective inhibitor of thrombin having a Ki of 0.6nM. For the synthesis of these compounds suitably protected aminoboronate derivatives were shown to be compatible with FMOC solid phase chemistry. (C) 1997 Elsevier Science Ltd.