Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity

Bioorg Med Chem Lett. 2008 Jun 1;18(11):3301-5. doi: 10.1016/j.bmcl.2008.04.036. Epub 2008 Apr 26.

Abstract

Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.

MeSH terms

  • Animals
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors*
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors*
  • Haplorhini
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Rats
  • Receptors, LHRH / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis*
  • Uracil / pharmacokinetics

Substances

  • Cytochrome P-450 CYP3A Inhibitors
  • Receptors, LHRH
  • Gonadotropin-Releasing Hormone
  • Uracil
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human