Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists

被引:58
作者
DeVita, RJ
Goulet, MT
Wyvratt, MJ
Fisher, MH
Lo, JL
Yang, YT
Cheng, K
Smith, RG
机构
[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA
[2] Merck Res Labs, Dept Biochem & Physiol, Rahway, NJ 07065 USA
关键词
D O I
10.1016/S0960-894X(99)00447-3
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Synthesis and in vitro activity of the enantiomers of quinolone GnRH antagonist (+/-) are reported. Chiral amino alcohols were prepared from the appropriate cyclic D- or L-amino acids by the Arndt-Eistert homologation followed by reduction of the resulting esters. Incorporation of these pharmacophores was achieved via a novel Mitsunobu alkylation of 4-hydroxyquinolones. The key amine pharmacophore for binding to the rat GnRH receptor was most active in the S-configuration. Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency. (C) 1999 Elsevier Science Ltd. Ail rights reserved.
引用
收藏
页码:2621 / 2624
页数:4
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