2. Academic Validation
  3. Discovery of an Orally Bioavailable Gonadotropin-Releasing Hormone Receptor Antagonist

Discovery of an Orally Bioavailable Gonadotropin-Releasing Hormone Receptor Antagonist

  • J Med Chem. 2016 Oct 13;59(19):9150-9172. doi: 10.1021/acs.jmedchem.6b01071.
Seon-Mi Kim 1,  Minhee Lee 1,  So Young Lee 1,  Euisun Park 2,  Soo-Min Lee 1,  Eun Jeong Kim 1,  Min Young Han 1,  Taekyung Yoo 1,  Jihyae Ann 3,  Suyoung Yoon 3,  Jiyoun Lee 4,  Jeewoo Lee 3
Affiliations

Affiliations

  • 1 Life Science R&D Center, SK Chemicals Company Ltd. , Seongnam-si, Gyeonggi-do, 463-400, Korea.
  • 2 Life Science Research Center, Daewoong Pharmaceutical Company Ltd. , Yongin-si, Gyeonggi-do, 449-814, Korea.
  • 3 Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
  • 4 Department of Global Medical Science, Sungshin University , Seoul 142-732, Korea.
PMID: 27608177 DOI: 10.1021/acs.jmedchem.6b01071
Abstract

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.

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