Discovery of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors
| Autor: | Shaoqing Chen, Paul Gillespie, Sung-Sau So, Steven Gregory Mischke, David Robert Bolin, Nam T. Le, Frank Mennona, Mushtaq Ahmad, Karin Conde-Knape, Charles Burghardt, Hong Wang, Shahid Tannu, Yimin Qian, Jarema Peter Kochan |
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| Rok vydání: | 2011 |
| Předmět: |
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
chemistry.chemical_classification Ketone biology High-throughput screening Organic Chemistry Clinical Biochemistry Pharmaceutical Science Fructose 6-phosphate Isoquinolines Biochemistry Glutamine Inhibitory Concentration 50 chemistry.chemical_compound chemistry Pharmacokinetics Enzyme inhibitor Drug Discovery biology.protein Molecular Medicine Potency Enzyme Inhibitors Molecular Biology Glutamine amidotransferase |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 21:6264-6269 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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