Novel analogues of degarelix incorporating hydroxy-, methoxy-, and pegylated-urea moieties at positions 3, 5, 6 and the N-terminus. Part III.
Novel analogues of degarelix incorporating hydroxy-, methoxy-, and pegylated-urea moieties at positions 3, 5, 6 and the N-terminus. Part III.
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地加瑞克的新型类似物，在位置 3、5、6 和 N 末端掺入羟基、甲氧基和聚乙二醇化脲部分。
DOI：
10.1021/jm060240a
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发表时间：
2006
影响因子：
7.3
通讯作者：
Rivier,Jean
中科院分区：
文献类型：
--
作者：
Samant,ManojP;Hong,DoleyJ;Croston,Glenn;Rivier,Catherine;Rivier,Jean
在报告基因试验中筛选新型地塞普利（Fe 200486）类似物的GnRH诱导反应拮抗作用（IC 50）。在去势雄性大鼠中测量促黄体生成素释放随时间的抑制。对Dab和Dap在3位（3−6）进行N ω-羟基-和N ω-甲氧基-氨基甲酰基化，并对4Aph在5位和6位（7− 10，15 − 17，22 −25）进行N ω-羟基-、Nω-甲氧基-氨基甲酰基化和聚乙二醇化。在N-末端使用不同的酰化基团（11− 14，18 − 21，26 −28）实现疏水性的调节。类似物8、15 - 17、22和23在体外与阿西林（IC 50 = 0.69 nM）和地塞普利（IC 50 = 0.58 nM）等效，类似物7、17和23的作用时间短于阿西林，而9、11、13、15、16和22的作用时间较长。只有9只和14只无组胺释放活性。没有类似物表现出与地舒利可相比的作用持续时间。鉴定了在HPLC（亲水性的衡量标准）上保留时间比地加瑞克更短和更长的类似物。
Novel degarelix (Fe200486) analogues were screened for antagonism of GnRH-induced response (IC50) in a reporter gene assay. Inhibition of luteinizing hormone release over time was measured in the castrated male rat.Nω-Hydroxy- andNω-methoxy-carbamoylation of Dab and Dap at position 3 (3−6), andNω-hydroxy-,Nω-methoxy-carbamoylation and pegylation of 4Aph at positions 5 and 6 (7−10,15−17,22−25) were carried out. Modulation of hydrophobicity was achieved using different acylating groups at the N-terminus (11−14,18−21,26−28). Analogues8,15−17,22, and23were equipotent to acyline (IC50= 0.69 nM) and degarelix (IC50= 0.58 nM) in vitro.Analogues7,17, and23were shorter acting than acyline, when9,11,13,15,16, and22were longer acting. Only9and14were inactive at releasing histamine. No analogue exhibited a duration of action comparable to that of degarelix. Analogues with shorter and longer retention times on HPLC (a measure of hydrophilicity) than degarelix were identified.