Lessons from Classical Inhibitors

As early as 1981, chemists at the Mitsubishi chemical company synthesized the thrombin inhibitor MD-805, 6 (Fig. 7.6), which has been extensively tested in humans under fhe name argatroban [34]. The compound, as might be seen from its 

Another early inhibitor is Napap, 7 (Fig. 7.7) [36]. The compound was synthesized as the racemate. The stereochemistry of the binding species was demonstrated by determining the structure in complex with alpha thrombin and was published by myself [13] and, at higher resolution in complex with epsilon thrombin, by Bode and Brandstetter [35]. 

This inhibitor can be considered a tetra-peptide analogue if the piperidine is taken as replacing a cyclized amino acid. 

MD-805 originated as a tripeptide with P2, Pl, and PT substituents. To prevent cleavage of the Pl-PT peptide bond, a secondary amide was introduced and optimized to the piperidine shown. What was not appreciated at the time was that the Pl arginine effectively jumped to P3. This is possible, as the structures show, but only if the arginine needle turns so that only one guanidine -NH2 interacts with Asp 189 (Fig. 7.9). 

In retrospect, this example reinforces a number of important principles  

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