A series of sulfonamide-based Factor Xa inhibitors demonstrated good in vitro anticoagulant activity, with compound 1f identified as a candidate for further evaluation based on its pharmacokinetic profile in rats and dogs.
Compound 1f was identified as a promising Factor Xa inhibitor candidate based on structure-activity relationships, in vitro activity, and favorable pharmacokinetics in animal models.
Factor Xa inhibitory activities for a series of N- (3S) -1- (1S) -1-methyl-2-morpholin-4-yl-2-oxoethyl-2-oxopyrrolidin-3-ylsulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.
Chan et al. (Tue,) reported a other. N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides was evaluated on Factor Xa inhibitory activities, pharmacokinetic profiles, and selectivity. A series of sulfonamide-based Factor Xa inhibitors demonstrated good in vitro anticoagulant activity, with compound 1f identified as a candidate for further evaluation based on its pharmacokinetic profile in rats and dogs.