Small-molecule inhibitor: argatroban

Name

History: The discovery of argatroban (as MD805) was described by Okamoto et al. (1981) and the compound was entered into a clinical trial not long after (Yamada, 1983).
Peptidases inhibited: Thrombin (S01.217), K_i 19 nM (Okamoto et al., 1981) or 85 nM (Brundish et al., 1999).
Mechanism: Inhibition is reversible. The mode of binding of argatroban (as MPQA) to thrombin has been characterised crystallographically by Bode et al. (1990).
Pharmaceutical relevance: Argatroban is one of the anti-coagulant agents that act as "direct" thrombin inhibitors (others being hirudin and melagatran). Anticoagulants that act less directly include warfarin, which interferes with the biosynthesis of the gamma-carboxyglutamate-containing coagulation factors, and heparin, which potentiates inhibition of thrombin by antithrombin. Argatroban is an approved drug for control of blood coagulation (LaMonte et al., 2005). It has also been suggested to alleviate herpes zoster-associated pain (Fujii et al., 2001) and to prevent tumor cell migration and bone metastasis (Asanuma et al., 2004).
DrugBank: DB00278

CID at PubChem: 92721
ChEBI: 610014
Structure
Chemical/biochemical name: (2S,4R)-1-[(2S)-5-(diaminomethylideneamino)-2-[(3-methyl-1,2,3,4- tetrahydroquinolin-8-yl)sulfonylamino]pentanoyl]-4- methyl-piperidine-2-carboxylic acid hydrate
Formula weight: 526

Comment: The stereo-configuration of the 4-methyl-2-piperidinecarboxylic acid portion of the molecule was found to have an unexpectedly profound effect on the inhibitory potency of the molecule (Okamoto et al., 1981). Immobilised argatroban has been used for the affinity purification of thrombin (Lefkowitz, 2005).
Reviews: Okamoto et al. (1981); Bode et al., 1990