Discovery of an Orally Bioavailable Gonadotropin-Releasing Hormone Receptor Antagonist

We
developed a compound library for orally available gonadotropin-releasing
hormone (GnRH) receptor antagonists that were based on a uracil scaffold.
On the basis of in vitro activity and CYP inhibition profile, we selected 18a (SKI2496) for further in vivo studies. Compound 18a exhibited more selective antagonistic activity toward
the human GnRH receptors over the GnRHRs in monkeys and rats, and
this compound also showed inhibitory effects on GnRH-mediated signaling
pathways. Pharmacokinetic and pharmacodynamic evaluations of 18a revealed improved bioavailability and superior gonadotropic
suppression activity compared with Elagolix, the most clinically advanced
compound. Considering that 18a exhibited highly potent
and selective antagonistic activity toward the hGnRHRs
along with favorable pharmacokinetic profiles, we believe that 18a may represent a promising candidate for an orally available
hormonal therapy.