Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1

被引：77

作者：

Whitby, Richard J.

Dixon, Sally

Maloney, Patrick R.

Delerive, Philippe

Goodwin, Bryan J.

Parks, Derek J.

Willson, Timothy M.

机构：

[1] GlaxoSmithKline Inc, Mol Discovery Res, Res Triangle Pk, NC 27709 USA

[2] Univ Southampton, Sch Chem, HANTS, Southampton SO17 1BJ, Hants, England

[3] GlaxoSmithKline Inc, Cardiovasc & Urogenital Ctr Excellence Drug Disco, F-91951 Les Ulis, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 23期

关键词：

D O I：

10.1021/jm060990k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the identification of substituted cis-bicyclo[ 3.3.0]-oct-2-enes as small molecule agonists of subfamily V orphan nuclear receptors ( NR5A), liver receptor homolog-1 ( LRH-1) and steroidogenic factor-1 ( SF-1). Using fluorescence resonance energy transfer ( FRET)based biochemical assays, compound 5a ( GSK8470) was identified as a high-affinity ligand for LRH-1 and SF-1. In liver cells, 5a increased the expression of the LRH-1 target gene small heterodimer partner ( SHP). Synthesis of analogues modified at three positions led to the development of compounds with functional selectivity between LRH-1 and SF-1.

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页码：6652 / 6655

页数：4

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