Inhibitory effect of JTV-803, a new cyclic guanidine derivative, on factorXa in vitro and in vivo

JTV-803, 4-[(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl]-1-(4-p yridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate showe d a competitive inhibitory effect on human factor Xa, with a K-i value of 0 .019 muM. This compound was 100 times more selective in inhibiting human fa ctor Xa as compared to its inhibitory activity against thrombin, plasmin, a nd trypsin. JTV-803 was also examined for its inhibitory effect on activate d factor Xa obtained from plasma of various animal species. JTV-803 exerted a potent inhibitory effect on human factor Xa (IC50: 0.081 muM). JTV-803 p rolonged activated partial thromboplastin time and prothrombin time in a do se-dependent manner. Oral anticoagulant efficacy of JTV-803 was examined ex vivo for its inhibition of human factor Xa in cynomolgus monkeys. JTV-803 produced more than 20% inhibition of human factor Xa for 8 h. Taken togethe r, the results indicate JTV-803 is a long-acting oral anticoagulant which e xerts its effect via specific inhibition of human factor Xa. (C) 2001 Elsev ier Science B.V. All rights reserved.