Mechanism-based thrombin inhibitors: design, synthesis, and molecular docking of a new selective 2-oxo-2H-1-benzopyran derivative

J Med Chem. 2007 Jul 26;50(15):3645-50. doi: 10.1021/jm061368v. Epub 2007 Jun 20.

Abstract

New 2-oxo-2H-1-benzopyran derivatives were prepared to optimize 2a,b, initially developed as mechanism-based alpha-chymotrypsin (alpha-CT) inhibitors, into potent and selective thrombin (THR) inhibitors. From this study, 22, characterized by a 2-(N-ethyl-2'-oxoacetamide)-5'-chlorophenyl ester side chain, was shown to be a good THR inhibitor (ki/KI = 3455 M(-1) x s(-1)), displaying an excellent selectivity profile against other serine proteases such as factor Xa, trypsin, and alpha-CT. Docking analysis of this compound into the different protein structures revealed the molecular basis responsible for its potency and selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Coumarins / chemical synthesis*
  • Coumarins / chemistry
  • Drug Design
  • Models, Molecular*
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors*
  • Thrombin / chemistry

Substances

  • 3-(5-chloro-2-(N-ethyloxoacetamido)phenoxycarbonyl)-6-chloromethylcoumarin
  • Benzopyrans
  • Coumarins
  • Thrombin