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Discovery of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors. 2011
Yimin Qian, and
Mushtaq Ahmad, and
Shaoqing Chen, and
Paul Gillespie, and
Nam Le, and
Frank Mennona, and
Steven Mischke, and
Sung-Sau So, and
Hong Wang, and
Charles Burghardt, and
Shahid Tannu, and
Karin Conde-Knape, and
Jarema Kochan, and
David Bolin
Department of Discovery Chemistry and Metabolic Diseases, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. yimin.qian@roche.com
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)=1μM) 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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