Discovery of 6-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): an orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R)

J Med Chem. 2009 Apr 9;52(7):2148-52. doi: 10.1021/jm801572m.

Abstract

A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-([4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl] methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Binding, Competitive
  • Biological Availability
  • Half-Life
  • Humans
  • In Vitro Techniques
  • Luteinizing Hormone / blood
  • Male
  • Microsomes, Liver / metabolism
  • Orchiectomy
  • Pituitary Gland / drug effects
  • Pituitary Gland / metabolism
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, LHRH / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 6-((4-(2-(4-tert-Butylphenyl)-1H-benzimidazol-4-yl)piperazin-1-yl)methyl)quinoxaline
  • Benzimidazoles
  • Quinoxalines
  • Receptors, LHRH
  • Luteinizing Hormone