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We describe the in vitro evaluation and crystallographic analysis of a new class of potent and selective, non-amino acid-based, small-molecule thrombin inhibitors, exemplified by 14. This class of achiral inhibitors lacks an amide-based backbone, exhibits nM inhibition of thrombin, and is selective for thrombin. Compound 14 does not interact with the active-site catalytic apparatus and is anchored to the enzyme via a single network of hydrogen bonds to Asp189 of the S1 pocket.

The structure–activity relationships of a novel series of non-amide-based thrombin inhibitors are described. Exploration of the P2 and the aryl binding region for this series has identified optimal groups for achieving nanomolar potency. The binding modes of these optimal groups have been confirmed by X-ray structural analysis.