Using the natural protein hirudin as a model, a novel class of synthetic peptide inhibitors were recently designed. These inhibitors, 'hirulogs', retain the carboxy terminal Hir53-64 domain that interacts with the anion binding exosite of thrombin, connected via an oligoglycyl spacer unit to a catalytic site-directed moiety modeled on the sequence [D]Phe-Pro-Arg-X. The scissile Arg-X bond bond of substrate-like inhibitors has been modified to the proteolytic-resistant functions as beta-homo amino acids Arg psi [CH2CONH] X (2) and reduced bond analogues Arg psi [CH2N]X (3). Both classes of compounds demonstrate inhibition of thrombin amidolytic activity, and this active-site inhibition is highly sensitive to the P1' residue X. Thus these hirulog derivatives are resistant to thrombin proteolysis while maintaining substrate-like interactions with the active center. Finally, hirulog derivatives with non-cleavable replacements of the scissile bond are found to be effective anticoagulant agents.