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.
Life Science R&D Center, SK Chemicals Company Ltd. , Seongnam-si, Gyeonggi-do, 463-400, Korea.
Seon-Mi
SM
Kim
Life Science R&D Center, SK Chemicals Company Ltd. , Seongnam-si, Gyeonggi-do, 463-400, Korea.
Minhee
M
Lee
Life Science R&D Center, SK Chemicals Company Ltd. , Seongnam-si, Gyeonggi-do, 463-400, Korea.
So Young
SY
Lee
Life Science Research Center, Daewoong Pharmaceutical Company Ltd. , Yongin-si, Gyeonggi-do, 449-814, Korea.
Euisun
E
Park
Life Science R&D Center, SK Chemicals Company Ltd. , Seongnam-si, Gyeonggi-do, 463-400, Korea.
Soo-Min
SM
Lee
Life Science R&D Center, SK Chemicals Company Ltd. , Seongnam-si, Gyeonggi-do, 463-400, Korea.
Eun Jeong
EJ
Kim
Life Science R&D Center, SK Chemicals Company Ltd. , Seongnam-si, Gyeonggi-do, 463-400, Korea.
Min Young
MY
Han
Life Science R&D Center, SK Chemicals Company Ltd. , Seongnam-si, Gyeonggi-do, 463-400, Korea.
Taekyung
T
Yoo
Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
Jihyae
J
Ann
Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
Suyoung
S
Yoon
Department of Global Medical Science, Sungshin University , Seoul 142-732, Korea.
Jiyoun
J
Lee
Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
Jeewoo
J
Lee
D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism
C484844:GNRHR protein, human; D006845:Hydrocarbons, Fluorinated; D011743:Pyrimidines; D011966:Receptors, LHRH; C000610579:SKI2852; C539351:elagolix; D000218:Adamantane