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Synthesis and Biological Evaluation of an Orally Bioavailable Gonadotropin-releasing Hormone (GnRH) Receptor Antagonist : 경구용 GnRH 수용체 길항제의 개발
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- Authors
- Advisor
- 이지우
- Major
- 약학대학 약학과
- Issue Date
- 2018-02
- Publisher
- 서울대학교 대학원
- Keywords
- Gonadotropin-releasing hormone ; GnRH receptor antagonist ; GnRH ; Sex hormone
- Description
- 학위논문 (박사)-- 서울대학교 대학원 : 약학대학 약학과, 2018. 2. 이지우.
- Abstract
- Part 1
We developed a compound library for orally available gonadotropin-releasing hormone (GnRH) receptor antagonists that were based on a uracil scaffold. Based on 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.
Part 2
We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the N-3 aminoethyl side chain and evaluated their antagonistic activity against human gonadotropin-releasing hormone (GnRH) receptors. Analogues with substituents at the ortho or meta position demonstrated potent in vitro antagonistic activity. Specifically, the introduction of a 2-OMe group enhanced nuclear factor of activated T-cells (NFAT) inhibition up to 6-fold compared to the unsubstituted analogue. We identified compound 12c as a highly potent GnRH antagonist with moderate CYP inhibition. Compound 12c showed potent and prolonged LH suppression after a single dose was orally administered in castrated monkeys. We believe that our SAR study offers useful insights to design GnRH antagonists as a potential treatment option for endometriosis.
- Language
- English
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