Department of Discovery Chemistry and Metabolic Diseases, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
Bioorg Med Chem Lett. 2011 Nov 1;21(21):6264-9. doi: 10.1016/j.bmcl.2011.09.009. Epub 2011 Sep 10.
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.
通过高通量筛选以及随后的命中鉴定和优化，我们合成了一系列 1-芳羰基-6,7-二甲氧基异喹啉衍生物，作为首次报道的强效和可逆的 GFAT 抑制剂。该类化合物的 SAR 研究表明，A 环和 C 环上的取代对 GFAT 抑制活性有显著影响。研究发现酮基对于高活性是必需的。化合物 28（RO0509347）在大鼠中表现出强效的 GFAT 抑制作用（IC50=1μM）和理想的药代动力学特性，并在 ob/ob 小鼠的 OGTT 试验中显示出显著的降低葡萄糖波动的功效。
