Small-molecule inhibitor: sepimostat mesilate

Name

History: An early reference to the development of sepimostat as a drug for pancreatitis was that of Marunaka et al. (1988).
Peptidases inhibited: K_i values reported were 0.097 microM for trypsin, 0.029 microM for kallikrein 1, 0.61 microM for plasma kallikrein, 0.57 microM for plasmin, 2.5 microM for thrombin, 20.4 microM for factor Xa and 6.4 microM for C1r. However, FUT-187 acted as a noncompetitive inhibitor for factor XIIa and an uncompetitive inhibitor for C1s, with K_i values of 0.021 and 0.18 microM, respectively.
Mechanism: Inhibition is reversible, and generally competitive (Nakamura et al., 1995).
Pharmaceutical relevance: Sepimostat can be administered orally, and has been evaluated as a possible drug for pancreatitis and other gastrointestinal conditions (see Literature).

CID at PubChem: 6918061
Structure
Chemical/biochemical name: (6-carbamimidoylnaphthalen-2-yl) 4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoate; methanesulfonic acid
Formula weight: 565

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).