PubMed · 2339737
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M Hellgren, L Hahn, T Dahlman. 1990. Thromboprophylaxis during pregnancy.. https://doi.org/10.1016/0002-9378(90)90050-h
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Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 1-[3-aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one 6f (BMS-740808), a highly potent (fXa Ki=30 pM) with a rapid onset of inhibition (2.7x10(7) M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa.
Heparins and vitamin K antagonist are the main antithrombotic agents used since several years. These two classes of drugs are very effective but not devoid of side effects and require either injections or regular laboratory controls. Therefore new agents have been developed. Two of these agents (fondaparinux and ximelagatran) are already available. Both are of non animal origin, do not induce thrombocytopenia and do not require laboratory controls. In recent studies fondaparinux has shown a better efficacy than low molecular weight heparin in major orthopedic interventions. Ximelagatran, which can be given orally, is now admitted also for short term use. It was hoped that it could replace vitamin K antagonists but increase of liver enzymes occurring after a few weeks is a major problem. Other new drugs are in advanced stage and will be also described.
A series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for P4 ligands in combination with a neutral biaryl P1 ligand were investigated with the 2-carboxyindole scaffold. A diverse set of P4 substituents was identified, which, in conjunction with a biaryl P1 ligand, gave highly potent factor Xa inhibitors, which were also selective versus other proteases and efficacious in various antithrombotic secondary assays.