Azaindoles: moderately basic P1 groups for enhancing the selectivity of thrombin inhibitors

Bioorg Med Chem Lett. 2003 Mar 10;13(5):795-8. doi: 10.1016/s0960-894x(03)00017-9.

Abstract

Starting from a 2-amino-6-methylpyridine P1 group and following a strategy of enlarging it whilst reducing its polarity, we have developed a series of potent, moderately basic azaindoles which are intrinsically much more selective for thrombin versus trypsin. Certain pyrazinone acetamide azaindole derivatives have pharmacokinetic parameters after oral administration to dogs, or efficacy in vitro, comparable to an optimized pyrazinone acetamide 2-amino-6-methylpyridine derivative.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Aza Compounds / chemistry*
  • Aza Compounds / pharmacokinetics
  • Aza Compounds / pharmacology*
  • Dogs
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Models, Molecular
  • Partial Thromboplastin Time
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thrombin / antagonists & inhibitors*
  • Thrombin / metabolism
  • Trypsin / metabolism

Substances

  • Aza Compounds
  • Enzyme Inhibitors
  • Indoles
  • Pyridines
  • Trypsin
  • Thrombin