Novel thrombin inhibitors incorporating non-basic partially saturated heterobicyclic P1-arginine mimetics

Bioorg Med Chem Lett. 2003 Mar 10;13(5):789-94. doi: 10.1016/s0960-894x(03)00030-1.

Abstract

The design, synthesis and biological activity of non-covalent thrombin inhibitors incorporating 4,5,6,7-tetrahydroindazole, 2-methyl-4,5,6,7-tetrahydroindazole, 4,5,6,7-tetrahydroisoindole, 5,6,7,8-tetrahydroquinazoline and 5,6,7,8-tetrahydroquinazolin-2-amine as novel, partially saturated, heterobicyclic P(1)-arginine side-chain mimetics is described. The binding mode of the most potent candidate in the series co-crystallized with human alpha-thrombin, which exhibited an in vitro K(i) of 140nM and more that 478-fold selectivity against trypsin, is discussed.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / chemistry*
  • Binding Sites
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / pharmacology
  • Cinoxacin / chemistry
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds, 2-Ring / chemistry*
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Hydrogen-Ion Concentration
  • Indazoles / chemistry
  • Indoles / chemistry
  • Models, Molecular
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thrombin / antagonists & inhibitors*
  • Thrombin / metabolism
  • Trypsin / metabolism

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds, 2-Ring
  • Indazoles
  • Indoles
  • Arginine
  • Trypsin
  • Thrombin
  • Cinoxacin