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.

我们构建了一款基于尿嘧啶（uracil）骨架的口服活性促性腺激素释放激素（gonadotropin-releasing hormone, GnRH）受体拮抗剂化合物库。基于体外活性与细胞色素P450（CYP）抑制谱，我们筛选得到化合物18a（SKI2496）用于后续体内研究。化合物18a对人类促性腺激素释放激素受体（hGnRHR）的拮抗活性，相较于其在猴与大鼠体内的GnRHR具有更高选择性；同时该化合物对GnRH介导的信号通路亦展现出抑制作用。对化合物18a开展的药代动力学与药效动力学评价结果显示，相较于当前临床进展最为领先的化合物艾拉戈利（Elagolix），其具备更优异的生物利用度与促性腺激素抑制活性。鉴于化合物18a对人类促性腺激素释放激素受体（hGnRHR）展现出强效且高选择性的拮抗活性，同时具备良好的药代动力学特性，我们认为该化合物有望成为一款极具开发前景的口服激素类治疗候选药物。