Structure- and property-based design of factor Xa inhibitors: Pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs

Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.

Graphical abstractThe synthesis and profiles of a series of fXa inhibitors with acyclic alanyl amide P4 motifs is described, which includes potent examples showing highly encouraging anticoagulant activity.Figure optionsDownload full-size imageDownload as PowerPoint slide