Novel non-covalent thrombin inhibitors incorporating P(1) 4,5,6,7-tetrahydrobenzothiazole arginine side chain mimetics

Eur J Med Chem. 2004 Mar;39(3):257-65. doi: 10.1016/j.ejmech.2003.12.006.

Abstract

The design, synthesis and biological activity of a series of novel non-covalent D-Phe-Pro-Arg motif-based thrombin inhibitors incorporating 4,5,6,7-tetrahydrobenzothiazol-2-amine as a novel arginine surrogate are described. Compound 9, the most potent in the series of thrombin inhibitors, exhibited an in vitro K(i) of 128 nM and 342-fold selectivity against trypsin. The binding mode of this novel class of thrombin inhibitors in the enzyme active site, based on the X-ray crystal structure of compound 9 co-crystallized with human alpha-thrombin, is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / chemistry*
  • Binding Sites
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / pharmacology*
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thiazoles / pharmacology*
  • Thrombin / antagonists & inhibitors*
  • Thrombin / metabolism
  • Trypsin / metabolism*

Substances

  • Enzyme Inhibitors
  • Thiazoles
  • Arginine
  • Trypsin
  • Thrombin