ABSTRACT
Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.
Subject(s)
Anticoagulants/pharmacology , Antithrombin III , Blood Coagulation/drug effects , Peptides/chemistry , Serine Proteinase Inhibitors/pharmacology , Administration, Oral , Animals , Anticoagulants/chemical synthesis , Antithrombin III/chemical synthesis , Antithrombin III/metabolism , Antithrombin III/pharmacology , Binding Sites , Blood Coagulation Tests , Dose-Response Relationship, Drug , Drug Design , Humans , Ligands , Microsomes, Liver/metabolism , Peptides/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Compound 7 was identified as the active metabolite of 6 by HPLC and mass spectral analysis. Modification of lead compound 7 by transformation of its N-oxide 6-6 biaryl ring system and fused aromatics produced a series of non-basic fXa inhibitors with excellent potency in anti-fXa and anticoagulant assays. The optimized compounds 73b and 75b showed sub to one digit micromolar anticoagulant activity (PTCT2). Particularly, anti-fXa activity was detected in plasma of rats orally administered with 1mg/kg of compound 75b.
