Design, synthesis and biological evaluation of selective boron-containing thrombin inhibitors

Based on the structural comparison of the S-l pocket in different trypsin-l ike serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro- X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesised as inhibitors of thrombin. The influence of hydrogen donor/acceptor properties of different residues in the P-1 side chain of th ese inhibitors on the selectivity profile has been investigated. This study confirmed the structure-based working hypothesis: The hydrophobic/hydrophi lic character of amino acid residues 190 and 213 in the neighbourhood of As p 189 in the S-1 pocket of thrombin (Ala/Val), trypsin (Ser/Val) and plasmi n (Ser/Thr) define the specificity for the interaction with different P-1 r esidues of the inhibitors. Many of the synthesised compounds demonstrate po tent antithrombin activity with Boc-D-trimethylsilylalanine-proline-boro-me thoxypropylglycine pinanediol (9) being the most selective thrombin inhibit or of this series. (C) 1999 Elsevier Science Ltd. All rights reserved.