Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, Italy.
Department of Medical Biotechnology and Translational Medicine, University of Milan, Via C. Saldini 50, 20133 Milano, Italy.
Molecules. 2023 May 3;28(9):3861. doi: 10.3390/molecules28093861.
Elagolix sodium salt is the first marketed orally active non-peptide gonadotropin-releasing hormone receptor antagonist (GnRHR-ant) for the management of hormone dependent diseases, such as endometriosis and uterine fibroids. Despite its presence on the market since 2018, a thorough NMR analysis of this drug, together with its synthetic intermediates, is still lacking. Hence, with the aim of filling this literature gap, we here performed a detailed NMR investigation, which allowed the complete assignment of the H, C, and N NMR signals. These data allowed, with the support of the conformational analysis, the determination of the stereochemical profile of the two atropisomers, detectable in solution. Moreover, these latter were also detected by means of cellulose-based chiral HPLC, starting from a sample prepared through an implemented synthetic procedure with respect to the reported ones. Overall, these results contribute to further understanding of the topic of atropisomerism in drug discovery and could be applied in the design of safe and stable analogs, endowed with improved target selectivity.
盐酸依戈洛昔纳是首个上市的具有口服活性的非肽类促性腺激素释放激素受体拮抗剂（GnRHR-ant），可用于治疗激素依赖性疾病，如子宫内膜异位症和子宫肌瘤。尽管自 2018 年以来该药物已上市，但对其进行全面的 NMR 分析，包括其合成中间体，仍然缺乏。因此，为了填补这一文献空白，我们在此进行了详细的 NMR 研究，完成了 H、C 和 N NMR 信号的完全归属。这些数据在构象分析的支持下，确定了在溶液中可检测到的两个对映异构体的立体化学特征。此外，还通过基于纤维素的手性 HPLC 从通过实施的合成程序制备的样品中检测到这些对映异构体，该程序相对于报道的方法有所改进。总的来说，这些结果有助于进一步了解药物发现中对映异构的主题，并可应用于设计具有更高靶选择性的安全稳定的类似物。
