Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position

J Med Chem. 1997 Nov 7;40(23):3726-33. doi: 10.1021/jm970493r.

Abstract

A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (Ki 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.

MeSH terms

  • Administration, Oral
  • Animals
  • Antithrombins / chemical synthesis*
  • Antithrombins / pharmacokinetics
  • Antithrombins / pharmacology*
  • Biological Availability
  • Crystallography, X-Ray
  • Dipeptides / chemical synthesis*
  • Dipeptides / pharmacokinetics
  • Dipeptides / pharmacology*
  • Dogs
  • Kinetics
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors*
  • Thrombin / metabolism

Substances

  • Antithrombins
  • Dipeptides
  • Pyridines
  • Thrombin