Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands

We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2′-({[4- (aminomethyl)phenyl]amino}carbonyl)-4′-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4′-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2 h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.

Non-amidine TF/FVIIa inhibitors were prepared and evaluated for inhibitory activity against TF/FVIIa in vitro and for plasma levels on oral administration in mice. Ex vivo anticoagulant activity and bleeding risk were also tested in cynomolgus monkeys by measuring PT, APTT and bleeding time.Figure optionsDownload as PowerPoint slide