Small-molecule inhibitor: DX-9065a

Name

Common name: DX-9065a
Other names: BX5633; (+)-2-[4-[(-1-acetimidoyl-4-piperidinyl)oxy]- 3-(7-amidino-2-naphthyl)propionic acid

History: DX-9065a was described as a novel inhibitor of blood coagulation by Nagahara et al. (1994).
Peptidases inhibited: Inhibits coagulation factor Xa very selectively. The K_i value for human factor Xa is 41 nM, compared to values (microM) for other human serine proteases thrombin > 2000, trypsin 0.62, chymotrypsin > 2000, plasmin 23, t-PA 21, plasma kallikrein 2.3 and tissue kallikrein 1000 (Hara et al., 1994). Also inhibited are the cysteine peptidases gingipain R and gingipain K (Matsushita et al., 2006).
Mechanism: Inhibition is reversible. The structural basis of the selective interaction of the inhibitor with factor Xa was investigated by Stubbs et al. (1995) and Brandstetter et al. (1996).
Pharmaceutical relevance: DX-9065a is a selective inhibitor of factor Xa, and as such, it inhibits the conversion of prothrombin to thrombin by factor Xa, and thus inhibits the conversion of fibrinogen to fibrin. Thrombin itself not only converts fibinogen to fibrin, but has a variety of other activities, and there are reasons to think that the inhibition of coagulation by inhibition of factor Xa may be preferable to inhibition of thrombin itself under some conditions (Nicolini et al., 1996; Komoriya et al., 2004). DX-9065a has been the subject of clinical trials (Alexander et al., 2005; Becker et al., 2006).

CID at PubChem: 698648
Structure
Chemical/biochemical name: (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]- 3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate
Formula weight: 228

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).
Reviews: Alexander & Singh (2005)