Uracils as potent antagonists of the human gonadotropin-releasing hormone receptor without atropisomers

被引：23

作者：

Guo, ZQ

Chen, YS

Huang, CQ

Gross, TD

Pontillo, J

Rowbottom, MW

Saunders, J

Struthers, S

Tucci, FC

Xie, Q

Wade, W

Zhu, YF

Wu, DP

Chen, C

机构：

[1] Neurocrine Biosci Inc, Dept Med Chem, San Diego, CA 92130 USA

[2] Neurocrine Biosci Inc, Dept Exploratory Res, San Diego, CA 92130 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 10期

关键词：

GnRH; antagonist; uracil; atropisomer;

D O I：

10.1016/j.bmcl.2005.03.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Uracil derivatives were designed and synthesized to avoid atropisomers observed in the 6-methyluracils as antagonists of the human GnRH receptor. Optimization at the 1- and 5-positions of the uracil resulted in potent compounds such as 24 (K-i = 0.45 nM). (c) 2005 Elsevier Ltd. All rights reserved.

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页码：2519 / 2522

页数：4

相关论文

共 18 条

[1]

BETZ SF, UNPUB J BIOL CHEM

[2] The expression, regulation and signal transduction pathways of the mammalian gonadotropin-releasing hormone receptor [J].

Cheng, KW ;

Leung, PCK .

CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, 2000, 78 (12) :1029-1052

[3]

Cottreau CM, 2003, CLIN CANCER RES, V9, P5142

[4]

Daniels J. M., 1997, Drug information journal : DIJ / Drug Information Association, V31, P639, DOI 10.1177/009286159703100303

[5] Residues within transmembrane helices 2 and 5 of the human gonadotropin-releasing hormone receptor contribute to agonist and antagonist binding [J].

Hoffmann, SH ;

ter Laak, T ;

Kühne, R ;

Reiländer, H ;

Beckers, T .

MOLECULAR ENDOCRINOLOGY, 2000, 14 (07) :1099-1115

[6] Gonadotropin-releasing-hormone-receptor antagonists [J].

Huirne, JAF ;

Lambalk, CB .

LANCET, 2001, 358 (9295) :1793-1803

[7] Aromatic interactions [J].

Hunter, CA ;

Lawson, KR ;

Perkins, J ;

Urch, CJ .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2, 2001, (05) :651-669

[8] A critical account on π-π stacking in metal complexes with aromatic nitrogen-containing ligands [J].

Janiak, C .

JOURNAL OF THE CHEMICAL SOCIETY-DALTON TRANSACTIONS, 2000, (21) :3885-3896

[9] GONADOTROPIN-RELEASING-HORMONE ANALOG DESIGN - STRUCTURE-FUNCTION STUDIES TOWARD THE DEVELOPMENT OF AGONISTS AND ANTAGONISTS - RATIONALE AND PERSPECTIVE [J].

KARTEN, MJ ;

RIVIER, JE .

ENDOCRINE REVIEWS, 1986, 7 (01) :44-66

[10] Gonadotropin-releasing hormone receptors [J].

Millar, RP ;

Lu, ZL ;

Pawson, AJ ;

Flanagan, CA ;

Morgan, K ;

Maudsley, SR .

ENDOCRINE REVIEWS, 2004, 25 (02) :235-275