Structure-activity relationship studies of gonadotropin-releasing hormone antagonists containing S-aryl/alkyl norcysteines and their oxidized derivatives.
Structure-activity relationship studies of gonadotropin-releasing hormone antagonists containing S-aryl/alkyl norcysteines and their oxidized derivatives.
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DOI：
10.1021/jm0613931
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发表时间：
2007-05
影响因子：
7.3
通讯作者：
M. Samant;Richard E. White;D. J. Hong;G. Croston;P. Conn;J. Janovick;J. Rivier
中科院分区：
文献类型：
--
作者：
M. Samant;Richard E. White;D. J. Hong;G. Croston;P. Conn;J. Janovick;J. Rivier
合成了一系列含有s -芳基化/烷基化去甲半胱氨酸的l-和d-异构体[Ncy(R)，其中R为2-萘基、甲基和异丙基]的1、4、7和10位的酰基类似物。其中一些类似物被一氧化和二氧化成亚砜和砜。在表达人GnRH受体的HEK-293细胞中，通过报告基因试验筛选了所有的阿昔林类似物对GnRH诱导反应的拮抗作用。9个类似物（9、11、15、16、17、19、20、21和22）的拮抗效力（IC50 < 2 nM）与acyline相似（IC50 = 0.52 nM）。选择的类似物（9、11、15、16、19和21）在体外通过报告基因试验和体内完整雄性大鼠试验测试其对大鼠GnRH-R的拮抗作用。类似物9和15在抑制睾丸激素水平方面最有效。
A series of acyline analogues incorporating l- and d-isomers of S-arylated/alkylated norcysteines [Ncy(R), where R is 2-naphthyl, methyl, and isopropyl] at positions 1, 4, 7, and 10 were synthesized. Some of these analogues were mono- and dioxidized to sulfoxides and sulfones. All of the analogues of acyline were screened for the antagonism of the GnRH-induced response in a reporter gene assay in HEK-293 cells expressing the human GnRH receptor. Nine of the analogues (9, 11, 15, 16, 17, 19, 20, 21, and 22) had antagonistic potency (IC50 < 2 nM) similar to that of acyline (IC50 = 0.52 nM) in this assay. Selected analogues (9, 11, 15, 16, 19, and 21) were tested in vitro for their antagonism at the rat GnRH-R in a reporter gene assay as well as in an in vivo intact male rat assay. Analogues 9 and 15 were the most potent in suppressing testosterone levels.