Chen Chen, Wu Dongpei, Guo Zhiqiang, Xie Qiu, Reinhart Greg J, Madan Ajay, Wen Jenny, Chen Takung, Huang Charles Q, Chen Mi, Chen Yongsheng, Tucci Fabio C, Rowbottom Martin, Pontillo Joseph, Zhu Yun-Fei, Wade Warren, Saunders John, Bozigian Haig, Struthers R Scott
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA.
J Med Chem. 2008 Dec 11;51(23):7478-85. doi: 10.1021/jm8006454.
The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
本文描述了一类新型的、带有丁酸的尿嘧啶苯乙胺类化合物作为强效人促性腺激素释放激素受体（hGnRH-R）拮抗剂的发现。该优化工作的一个主要重点是在保持这些尿嘧啶对GnRH-R的活性的同时，改善它们对CYP3A4的抑制作用。R-4-{2-[5-(2-氟-3-甲氧基苯基)-3-(2-氟-6-[三氟甲基]苄基)-4-甲基-2,6-二氧代-3,6-二氢-2H-嘧啶-1-基]-1-苯乙氨基}丁酸钠盐，即10b（艾拉戈利），被鉴定为一种强效且选择性的hGnRH-R拮抗剂。在去势猕猴中口服10b可抑制促黄体生成素。这些研究工作促使10b被确定为一种用于治疗子宫内膜异位症的临床化合物。
