Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1370397 | Bioorganic & Medicinal Chemistry Letters | 2011 | 6 Pages |
Abstract
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 (IC50 = 1 μM) with a desirable pharmacokinetic profile in rats, and showed significant efficacy in reducing the glucose excursion in an OGTT test in ob/ob mice.
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Related Topics
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Authors
Yimin Qian, Mushtaq Ahmad, Shaoqing Chen, Paul Gillespie, Nam Le, Frank Mennona, Steven Mischke, Sung-Sau So, Hong Wang, Charles Burghardt, Shahid Tannu, Karin Conde-Knape, Jarema Kochan, David Bolin,