Bioorganic & Medicinal Chemistry 2000-09-01

Selective boron-containing thrombin inhibitors--X-ray analysis reveals surprising binding mode.

A von Matt, C Ehrhardt, P Burkhard, R Metternich, M Walkinshaw, C Tapparelli

Index: Bioorg. Med. Chem. 8(9) , 2291-303, (2000)

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Abstract

Based on the structural comparison of the S1 pocket in different trypsin-like serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesized as inhibitors of thrombin. Among the novel compounds, a number of derivatives were synthesized which appeared to have side-chain variants too big to fit into the S1 pocket. Nevertheless, these compounds inhibited thrombin in the nM range. The X-ray structure of one of these inhibitors bound to the active side of thrombin reveals that a new binding mode is responsible for these surprising results.