Small-molecule inhibitor: benzamidine

Name

History: It was reported by Inagami & Murachi (1963) that trypsin is inhibited by both aliphatic and aromatic alkylamines, and inhibition constants for benzamidine and many analogues were described by Markwardt et al. (1968).
Peptidases inhibited: Trypsin, plasmin and thrombin, with K_i commonly in the range 10 - 40 micromolar (Markwardt et al., 1968). Other serine peptidase with trypsin-like specificity also are inhibited.
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Many inhibitors of coagulation enzymes that are potential leads to drugs contains benzamidine functionality (e.g. Koshio et al., 2005).
DrugBank: DB03127

Inhibitor class: This compound is of the benzamidine class. Such compounds are reversible inhibitors of trypsin and many other peptidases that show selectivity for arginine, or possibly lysine, in P1. The cationic amidino group of the inhibitor interacts with a carboxylate located in the bottom of the S1 subsite, and there are also hydrophobic interactions with the sides of the S1 pocket (Krieger et al., 1974; Bode & Schwager, 1975).
Comment: 4-Aminobenzamidine (Compound 2) is a slightly more potent inhibitor of trypsin than benzamidine itself (Markwardt et al. (1968)), and is readily coupled to Sepharose to create an affinity medium for purification of trypsin-like peptidases (Schmer, 1972). Benzamidine (1 mM) is a common component of mixtures of inhibitors designed to suppress peptidase activity in biological samples.
Reviews: Powers & Harper (1986), pp. 78 - 82.