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

Bioorg Med Chem Lett. 2006 Dec 1;16(23):5953-7. doi: 10.1016/j.bmcl.2006.09.001. Epub 2006 Sep 18.

Abstract

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.

MeSH terms

  • Alanine / chemistry*
  • Amides / chemistry*
  • Anticoagulants / chemical synthesis
  • Anticoagulants / chemistry
  • Anticoagulants / metabolism
  • Anticoagulants / pharmacology
  • Antithrombin III / chemical synthesis*
  • Antithrombin III / chemistry
  • Antithrombin III / metabolism
  • Antithrombin III / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • Factor Xa / chemistry
  • Factor Xa / metabolism
  • Models, Molecular
  • Molecular Structure
  • Pyrroles / chemistry*
  • Structure-Activity Relationship

Substances

  • Amides
  • Anticoagulants
  • Pyrroles
  • Antithrombin III
  • Factor Xa
  • Alanine