Identification of structural features for 4-methyl-3-(6-[phenyl methylene] amino} pyridine-3-yl)-2H chromen-2-one derivatives as clotting factor Xa inhibitors.

Anticoagulants are used to prevent the formation and extension of blood clots in various disorders as prophylactic agents for thrombo-embolic disorders. Designing of specific inhibitors against molecular targets that play a pivotal role in the coagulation cascade is indispensable. Clotting Factor Xa is one such attractive target for the design of new oral anticoagulants because of the unique role factor Xa plays in the coagulation cascade as a connection between the extrinsic and intrinsic pathways. Application of computational techniques in drug discovery process helps in identifying parameters which can lead to achieve better pharmacological profile. The docking interactions and QSAR studies performed on series of 4-methy-3-(6-[phenyl methylene] amino} pyridine-3-yl)-2H chromen-2-one derivatives provide significant insights for designing of better ligands as anticoagulants.

2-aminomethylphenylamine as a novel scaffold for factor Xa inhibitor.

We have been researching orally active factor Xa inhibitor for a long time. We explored the new diamine linker using effective ligands to obtain a new attractive original scaffold 2-aminomethylphenylamine derivative. Compound 1D showed very strong in vitro and in vivo factor Xa inhibitory activity, as well as favorable PK profiles in po administration to monkeys.

From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3.

Highly potent and selective substrate analogue factor Xa inhibitors were obtained by incorporation of non-basic or modestly basic P1 residues known from the development of thrombin inhibitors. The modification of the P2 and P3 amino acids strongly influenced the selectivity and provided potent dual factor Xa and thrombin inhibitors without affecting the fibrinolytic enzymes. Several inhibitors demonstrated excellent anticoagulant efficacy in standard clotting assays in human plasma.

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 2h 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.

Dose-dependent antithrombotic activity of an orally active tissue factor/factor VIIa inhibitor without concomitant enhancement of bleeding propensity.

The discovery of a highly potent and selective tissue factor/factor VIIa inhibitor is described. Upon oral administration of its double prodrug in the guinea pig, a dose-dependent antithrombotic effect is observed in an established model of arterial thrombosis without prolonging bleeding time. The pharmacodynamic properties of this selective inhibitor are compared to the behaviour of a mixed factor VIIa/factor Xa inhibitor.