DESIGN OF A NOVEL CLASS OF BIFUNCTIONAL THROMBIN INHIBITORS, SYNTHESIZED BY THE FIRST APPLICATION OF PEPTIDE BORONATES IN SOLID-PHASE CHEMISTRY

Borologs containing peptide boronates are new bifunctional biologicall y active molecules which bind to and inhibit thrombin. These compounds are designed based on the C-terminal sequence of hirudin. The inhibit ors consists of four parts, i) an active site inhibitor, D-Phe Pro-Bor o(aa)-OPin. ii) an anion binding exosite association moiety, Hirudin, iii) a spacer to link these components and iv) a novel 'flexor' non-pe ptide unit to allow correct orientation. The bivalent nature of the in hibitor [-D-PheProBoroBpgOPin]CO(CH2)(3)COGly(2)Hir enhanced binding u p to 10 fold greater than the corresponding native peptide Z-D-PheProB oroBpgOPin 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 chemist ry. (C) 1997 Elsevier Science Ltd.