Metabolism investigation leading to novel drug design: orally active prostacyclin mimetics. Part 4

Bioorg Med Chem Lett. 2005 Jul 1;15(13):3284-7. doi: 10.1016/j.bmcl.2005.04.076.

Abstract

A metabolism study of FR181157 (1) led to the discovery of new oxazole derivatives as active metabolites. The metabolite 6 with an epoxy ring exhibited high anti-aggregative potency with an IC(50) of 5.8 nM and potent binding affinity for the human recombinant IP receptor with a K(i) value of 6.1 nM and selectivity for human IP receptor over all other members of the human prostanoid receptor family.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Biotransformation
  • Drug Design
  • Epoprostenol / agonists
  • Epoprostenol / antagonists & inhibitors*
  • Humans
  • Inhibitory Concentration 50
  • Microsomes, Liver / metabolism
  • Molecular Mimicry
  • Oxazoles / pharmacokinetics*
  • Oxazoles / pharmacology
  • Pharmacokinetics
  • Platelet Aggregation / drug effects
  • Rats
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Oxazoles
  • PTGIR protein, human
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin
  • Epoprostenol