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

Bioorg Med Chem Lett. 2011 Mar 15;21(6):1582-7. doi: 10.1016/j.bmcl.2011.01.131. Epub 2011 Feb 1.

Abstract

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.

MeSH terms

  • Drug Design
  • Factor Xa Inhibitors*
  • Models, Molecular
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology*
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Factor Xa Inhibitors
  • Pyrrolidines
  • Serine Proteinase Inhibitors