Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.

Graphical abstractThe discovery of a potent series of orally available Factor Xa inhibitors with monoaryl P4 motifs is described.Figure optionsDownload full-size imageDownload as PowerPoint slide