Structure and property based design of factor Xa inhibitors: Pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs

The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.

Graphical abstractThe discovery of potent series of orally available factor Xa inhibitors with aminoindane and phenylpyrrolidine motifs is described.Figure optionsDownload full-size imageDownload as PowerPoint slide