Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines

被引：384

作者：

Collins, JL ^{[1
]}

Fivush, AM ^{[1
]}

Watson, MA ^{[1
]}

Galardi, CM ^{[1
]}

Lewis, MC ^{[1
]}

Moore, LB ^{[1
]}

Parks, DJ ^{[1
]}

Wilson, JG ^{[1
]}

Tippin, TK ^{[1
]}

Binz, JG ^{[1
]}

Plunket, KD ^{[1
]}

Morgan, DG ^{[1
]}

Beaudet, EJ ^{[1
]}

Whitney, KD ^{[1
]}

Kliewer, SA ^{[1
]}

Willson, TM ^{[1
]}

机构：

[1] GlaxoSmithKline, Res Triangle Pk, NC 27709 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 10期

关键词：

D O I：

10.1021/jm0255116

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A potent, selective, orally active LXR agonist was identified from focused libraries of tertiary amines. GW3965 (12) recruits the steroid receptor coactivator 1 to human LXRalpha in a cell-free ligand-sensing assay with an EC50 of 125 nM and profiles as a full agonist on hLXRalpha and hLXRbeta in cell-based reporter gene assays with EC50's of 190 and 30 nM, respectively. After oral dosing at 10 mg/kg to C57BL/6 mice, 12 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concentrations of HDL cholesterol by 30%. 12 will be a valuable chemical tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metabolism.

引用

页码：1963 / 1966

页数：4

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