Small-molecule inhibitor: PKSI-527

Name

History: PKSI-527 was discovered as a potent inhibitor of plasma kallikrein by Wanaka et al. (1990).
Peptidases inhibited: PKSI-527 (termed Tra-Phe-APAA) inhibited plasma kallikrein with a K_i value of 0.81 microM, while it inhibited kallikrein 1, plasmin, u-plasminogen activator, factor Xa and thrombin with Ki values of >500, 390, 200, >500, and >500 microM, respectively. However, its stereoisomer containing the D-Phe residue did not exhibit any detectable inhibitory activity (Wanaka et al., 1992).
Mechanism: Inhibition is reversible, and presumably competitive. Crystal structures of complexes with trypsin show how PKSI-527 interacts with the inhibited peptidase (Nakamura et al., 1995; Tomoo et al., 2001), the amino group of the aminomethylcyclohexanecarboxylic acid moiety being particularly important.
Pharmaceutical relevance: It has been suggested that the combination of NO donor and PKSI-527 may have clinical antithrombotic potential (Ikarugi et al., 2005).

CID at PubChem: 3035562
Structure
Chemical/biochemical name: 2-[4-[[(2S)-2-[[4-(aminomethyl)cyclohexanecarbonyl]amino]-3-phenyl-propanoyl]amino]phenyl]acetic acid hydrochloride; trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanine-4-carboxymethylanilide
Formula weight: 473

Comment: trans-4-Aminomethylcyclohexanecarboxylic acid is tranexamic acid, known as an inhibitor of plasmin. PKSI-527 is used in the affinity chromatograph of plasma kallikrein (Tada et al., 2001) and to investigate the functions of plasma kallikrein (e.g. Hashimoto et al., 2003).