Discovery of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors

被引：18

作者：

Qian, Yimin ^{[1
]}

Ahmad, Mushtaq ^{[1
]}

Chen, Shaoqing ^{[1
]}

Gillespie, Paul ^{[1
]}

Le, Nam ^{[1
]}

Mennona, Frank ^{[1
]}

Mischke, Steven ^{[1
]}

So, Sung-Sau ^{[1
]}

Wang, Hong ^{[1
]}

Burghardt, Charles ^{[1
]}

Tannu, Shahid ^{[1
]}

Conde-Knape, Karin ^{[1
]}

Kochan, Jarema ^{[1
]}

Bolin, David ^{[1
]}

机构：

[1] Hoffmann La Roche Inc, Dept Discovery Chem & Metab Dis, Nutley, NJ 07110 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 21期

关键词：

Glutamine fructose-6-phosphate amidotransferase (GFAT); Isoquinoline derivatives; Photo cyclization; Enzyme inhibitor; Diabetes target; Oral glucose tolerance test (OGTT); INSULIN-RESISTANCE; GLUTAMINEFRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE; PRODUCTS; GLUCOSE; GENE;

D O I：

10.1016/j.bmcl.2011.09.009

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Through high throughput screening and subsequent hit identification and optimization, we synthesized a series of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as the first reported potent and reversible GFAT inhibitors. SAR studies of this class of compounds indicated significant impact on GFAT inhibition potency by substitutions on the A-ring and C-ring. The ketone group was found to be necessary for high potency. Compound 28 (RO0509347) demonstrated potent GFAT inhibition (IC(50) = 1 mu M) with a desirable pharmacokinetic profile in rats, and showed significant efficacy in reducing the glucose excursion in an OGTT test in ob/ob mice. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6264 / 6269

页数：6

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